Which autoimmune conditions are palliated by pregnancy, which are exacerbated by pregnancy, and which have postpartum exacerbations?
RA and Graves disease seem to be palliated by pregnancy. SLE is exacerbated by pregnancy. Graves disease and myasthenia gravis are notorious for postpartum exacerbations.
Pregnancy increases the likelihood of SLE flares. The risk is highest in early pregnancy and during puerperium, with relative quiescence in the latter half of pregnancy. A lupus flare may be difficult to distinguish from pregnancy-induced HTN, as the features of HTN, edema, and proteinuria are shared. What lab value can help with this distinction?
Complement levels are low in SLE flare and normal in PIH.
Mortality is increased in pregnancy women with SLE, with most deaths occuring as a result of ___.
Mortality is increased in pregnancy women with SLE, with most deaths occuring as a result of pulmonary hemorrhage due to lupus pneumonitis and other complications (transverse myelitis, stroke, corticosteroid complications).
In addition to an increased incidence of IUGR and preterm labor, neonates born to mothers with SLE have a risk of congenital heart block. Why?
Antibodies to SS-A and SS-B (Ro and La) are thought to mediate this complication.
What laboratory investigations are often undertaken following two or more spontaneous abortions?
Parental karyotyping (karyotyping of an abortus is often indicated as well). Endometrial bxs may be obtained to exclude luteal phase defect (endometrial histology that is 2 or more days discrepant with dates). Endometrial culture may be obtained to exclude subclinical infection with U. urealyticum or C. trachomatis. Thyroid function tests. Tests for lupus anticoagulants.
CD5 is expressed by normal and neoplastic T cells (not expressed by very immature T cells) and a small, normally inconspicuous, B cells subset. In what non-malignant situation can patients have circulating CD19+/CD20+/CD5+ B cells?
Occasionally, patients have increased polyclonal benign circulating CD19+/CD20+/CD5+ B cells, particularly in rheumatoid arthritis.
What is the most frequent autoimmune disorder associated with ovarian teratomas?
Autoimmune encephalitis due to antibodies against the N-methyl-D-aspartate receptor (anti-NMDAR), a condition that frequently involves temporal lobes and hippocampus.
Its recognition is important, as removal of the ovarian tumor and early immunosuppressive therapy will often improve the outcome, with full recovery or only a residual mild neurologic deficit.
Goodpasture disease refers to the triad of ___, ___, and ___.
Goodpasture disease refers to the triad of pulmonary (alveolar) hemorrhage, glomerulonephritis of any severity, and serum anti-GBM production. The treatment of choice is plasmapheresis.
Goodpasture disease refers to the triad of pulmonary (alveolar) hemorrhage, glomerulonephritis of any severity, and serum anti-GBM production. What are these circulating antibodies directed against?
The NC1 domain of collagen IV in glomerular and alveolar basement membranes.
What 3 major categories of small vessel vasculitis can cause the pulmonary-renal syndrome?
Anti-GBM disease, ANCA disease, and immune complex-mediated diseases (such as SLE).
What is pulmonary-renal syndrome? What are causes of it?
The combination of acute glomerulonephritis and pulmonary hemorrhage. Causes: ANCA-positive vasculitis (granulomatosis with polyangiitis/Wegener’s, microscopic polyangiitis). Anti-GBM disease (Goodpasture’s). Pulmonary hemorrhage is a rare finding in lupus, HSP (IgAV), and infective endocarditis. Acute glomerulonephritis complicated by pulmonary edema due to fluid overload, as can occur in poststreptococcal glomerulonephritis.
What are 3 disorders in which linear IgG staining may be seen in glomeruli?
Diabetic glomerulosclerosis, fibrillary glomerulopathy, anti-GBM disease.
To what are c-ANCA and p-ANCA antibodies directed against?
c-ANCA: proteinase 3. p-ANCA: myeloperoxidase.
The Chapel Hill consensus conference recommendation on the nomenclature of systemic vasculitides is based primarily based on what?
It is based on the caliber of the most inflamed/affected vessels (the system does additionally incorporate IF findings and selected clinical/lab parameters). Small vessel vasculitis refers to changes found in distal vascular branches including arterioles, capillaries and venules. Medium vessel vasculitis is found in the main muscular arterial segments with multiple medial smooth muscle layers. Large vessel vasculitis is seen in the aorta and its largest branches.
What is the most common form of vasculitis in patients older than 50?
Giant cell arteritis (formerly termed temporal arteritis).
Giant cell arteritis (formerly termed temporal arteritis) is a granulomatous form of ANCA-negative large vessel vasculitis. What vessels does it tend to affect?
The aorta and its major branches, especially the extracranial arteries.
Giant cell arteritis (formerly termed temporal arteritis) tends to affect the aorta and its major branches, especially the extracranial arteries. Histologic appearance?
The inflammatory process, composed of mononuclear cells with a predominance of macrophages and lymphocytes, originates in the media and extends into the intima and adventitia. Multinucleated giant cells, of either the Langerhans or foreign body type, are found in about half of cases, often adjacent to the fragmented internal elastic lamina. Fibrinoid vascular wall necrosis is an infrequent observation and, when present, it patchy in distribution. GCA involves arteries in a segmental fashion, so a minimum of a 3 cm long segment should be obtained for an adequate histologic examination.
Giant cell arteritis is an ANCA-negative large vessel vasculitis. Is extensive fibrinoid necrosis consistent with giant cell arteritis?
No. In GCA, fibrinoid vascular wall necrosis is an infrequent observation and, when present, is patchy in distribution. The presence of extensive fibrinoid necrosis should raise the possibility of another type of systemic ANCA-negative vasculitis found in medium-sized vessels, such as polyarteritis nodosa.
When are antiphospholipid syndromes classified as primary, and when are they classified as secondary?
APS are classified as primary if they present with only a hypercoagulable state, and are classified as secondary if they are accompanied by other autoimmune disorders, such as SLE or other connective tissue diseases.
In antiphospholipid antibody syndrome, venous thrombosis is typically seen in deep leg veins (__%), as well as renal, hepatic, and retinal veins. Arterial thrombosis is typically seen in cerebrovascular (__%), coronary (__%), as well as ocular, mesenteric, deep leg, and renal arteries.
In antiphospholipid antibody syndrome, venous thrombosis is typically seen in deep leg veins (55%), as well as renal, hepatic, and retinal veins. Arterial thrombosis is typically seen in cerebrovascular (50%), coronary (25%), as well as ocular, mesenteric, deep leg, and renal arteries.
What is “catastrophic antiphospholipid syndrome”?
In rare instances (less than 1% of cases), multiple organ sites are affected by thrombosis simultaneously with dramatic clinical consequences and a mortality rate of up to 50%.
Thrombotic microangiopathy -a descriptive term- characterizes stenosing and/or thrombotic changes in small vessels (capillaries, arterioles, pre-arterioles, and small arteries). Veins and larger arteries with multiple layers of medial smooth muscle cells are characteristically spared. What are histologic features of the acute phase of a TMA?
The acute phase of a TMA is characterized by various changes that can be seen individually or in combination: (1) endothelial cell swelling and “mucoid” intimal widening with severe narrowing of vascular lumens; (2) intraluminal fibrin thrombi and/or fragmented RBCs in the intima and media; (3) necrosis of individual endothelial or medial smooth muscle cells; (4) PAS-positive nodular proteinaceous deposits replacing single necrotic arteriolar smooth muscle cells. Note: fibrin thrombi may sometimes be detected but they are not essential for establishing the diagnosis of a TMA.
Why is the “thrombotic” in thrombotic microangiopathy sometimes a misnomer?
Fibrin thrombi may sometimes be detected but they are not essential for establishing the diagnosis of a TMA.
The thrombotic microangiopathies are microvascular occlusive disorders characterized by systemic or intrarenal aggregation of platelets, thrombocytopenia, and mechanical injury to erythrocytes. TTP and HUS are both TMAs; What distinguishes them?
TTP affects mainly adults, with systemic microvascular aggregation of platelets affecting primarily the brain. HUS affects mainly children, with platelet–fibrin thrombi occluding predominantly the renal circulation.
The initial common event in the pathogenesis of all forms of thrombotic microangiopathy is severe endothelial cell injury that is caused by a wide variety of different agents. How reliably can the pathologist identify the underlying causative agent or event?
The pathologist generally cannot reliably identify the underlying causative agent or event and can often render only a descriptive diagnosis of TMA. The clinical distinction is not always clear-cut either and they are often clinically referred to as TTP-HUS.
Infection with EBV induces production of antibodies including IgG and IgM anti-viral capsid Ag (anti-VCA), anti-i, RF, ANA, and the Paul-Bunnell heterophile antibody. How sensitive and specific are heterophile Ab for EBV infection?
The heterophile Ab is fairly specific but not very sensitive for EBV infection, being present in 80% of infected teens and adults, 40% of all infected children, and 20% of infected children under 4.
Infection with EBV induces production of antibodies including IgG and IgM anti-viral capsid Ag (anti-VCA), anti-i, RF, ANA, and the Paul-Bunnell heterophile antibody. When do heterophile Ab become detectable, and for how long do they remain detectable?
? They emerge during the first week of symptoms, 3-4 wks after infection, and return to undetectable levels by 3-6 mos. ? They present in peak levels 2-6 wks after primary infection, and they may remain positive in low levels for up to a year.
What conditions can give a false positive Monospot test?
Toxoplasmosis, rubella, CMV, HIV, SLE, RA, lymphoma/leukemia.
What are the serologic markers for EBV? Do they have good sensitivity and specificity?
IgG and IgM anti-viral capsid antigen (anti-VCA). IgG anti-EBV early antigen (EBV-EA). IgG anti-EBV nuclear antigen (EBNA). These have very high sensitivity (>94%) and specificity (>95%) for EBV infectious mononucleosis.
What is the pattern of EBV serologic tests in primary infection?
Following infection, the first marker to appear is IgM anti-VCA. IgG anti-VCA emerges shortly after the IgM and slightly before the heterophile antibody. IgG anti-EA and IgG anti-EBNA begin to appear 1 to 2 months into infection. IgG anti-EBNA and IgG anti-VCA persist indefinitely.
For the EBV infectious stages (early acute, acute, convalescent, and remote), give the positivity and negativity for: heterophile Ab, IgM anti-VCA, IgG anti-VCA, IgG anti-EA, IgG anti-EBNA.
Early acute: -/+, +, +, -, -. Acute: +/-, +, +, +, -/+. Convalescent: -, -, +, +, +. Remote: -, -, -/+, +, +.
In EBV infection, IgG antibodies to early antigen (IgG anti-EA) are present at the onset of clinical illness. What are the two subsets of EA IgG?
There are two subsets of EA IgG: anti-D and anti-R. The presence of anti-D antibodies is consistent with recent infection since titers disappear after recovery, but their absence does not exclude acute illness because the antibodies are not expressed in a significant number of patients. Anti-R antibodies are only occasionally present in IM.
What is the EBER immunostain?
EBV-encoded RNA; nuclear RNA portions of EBER 1 and 2 genes. Nuclear stain.
How do the EBER and LMP1 immunostains stain Hodgkin lymphoma?
EBER is located to the nuclei of RS/H cells, with little to no expression in the background small lymphocytes. LMP1 is expressed in the cytoplasm and surface membrane of RS/H cells but is rarely expressed in latently infected background lymphocytes of Hodgkin lymphoma.
What are Digoxin-Like Immunoreactive Substances (DLIS) / Endogenous Digoxin-Like Substances (EDLS)?
They are endogenous or exogenous substances that cross-react with antidigoxin antibodies and falsely elevate serum digoxin concentrations, interfering in interpretation of results for therapeutic digoxin monitoring. Falsely lower digoxin values due to the presence of DLISs have been reported as well.
Digoxin-Like Immunoreactive Substances (DLIS) / Endogenous Digoxin-Like Substances (EDLS) are endogenous or exogenous substances that cross-react with antidigoxin antibodies and falsely elevate serum digoxin concentrations, interfering in interpretation of results for therapeutic digoxin monitoring. In what populations/conditions is it seen?
Elevated DLIS concentrations are encountered in patients with volume-expanded conditions such as uremia, essential hypertension, liver disease, and preeclampsia. They are also seen in neonates, pregnant women, and renal failure.
What drugs are identified as definitely causing drug-induced lupus?
Procainamide, hydralazine, minocycline, diltiazem, penicillamine, isoniazid (INH), quinidine, anti-tumor necrosis factor (TNF) alpha therapy (most commonly with infliximab and etanercept), interferon-alfa, methyldopa, chlorpromazine, and practolol.
Is the most common cause of the pulmonary-renal vasculitic syndrome ANCA disease or anti-GBM disease?
ANCA disease accounts for ~55% of cases, anti-GBM for 7%, and both ANCA and anti-GBM present in 8% of cases.
In the past, polyarteritis nodosa and what is now termed microscopic polyangiitis were used synonymously. What are the current definitions according to the Chapel Hill nomenclature system?
PAN is defined as an “ANCA-negative” necrotizing arteritis without immune complex deposits that primarily affects medium-sized arteries. Microscopic polyangiitis is defined as a (commonly) ANCA-positive necrotizing vasculitis without immune deposits that affects small vessels including capillaries.
What are the 3 major ANCA-associated, necrotizing small vessel vasculitides not associated with the deposition of immune complex deposits?
Wegener’s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome.
The 3 major ANCA-associated, necrotizing small vessel vasculitides not associated with the deposition of immune complex deposits are Wegener’s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. How are these 3 differentiated?
Clinical features. Patient’s lacking signs of asthma, lung and sinus inflammation, or peripheral blood eosinophilia are best classified as having microscopic polyangiitis. Necrotizing inflammatory lesions involving the lungs, nasal sinuses and kidneys are typically seen in cases of Wegener’s granulomatosis. Peripheral blood eosinophilia and asthma are defining features of Churg-Strauss syndrome.
What are the 2 types of ANCA assays used?
Indirect immunofluorescence assay (IIA), using alcohol fixed buffy coat leukocytes, and enzyme-linked immunosorbent assay (ELISA), using purified specific antigens. The IIA is more sensitive and the ELISA more specific. The optimal approach to clinical testing for ANCA is therefore to screen with IIF assays, if available, and to confirm all positive results with ELISAs directed against the vasculitis-specific target antigens (PR3 and MPO).
In vasculitis, the two relevant target antigens are proteinase 3 (PR3) and myeloperoxidase (MPO). Where are these antigens located?
Both PR3 and MPO are located in the azurophilic granules of neutrophils and the peroxidase-positive lysosomes of monocytes. Antibodies with target specificities for PR3 and MPO are called PR3-ANCA (c-ANCA) and MPO-ANCA (p-ANCA), respectively.
In generalized granulomatosis with polyangiitis (GPA) (Wegener’s granulomatosis), what % of patients are ANCA positive? And what type of ANCA do they have?
~90% of patients with active, generalized GPA are ANCA-positive. There is a small subset of patients with active, generalized GPA who do not have ANCA. Furthermore, in limited forms of the disease (such as subsets in which upper respiratory tract disease predominates and renal involvement is absent), up to 40% of patients may be ANCA-negative. Thus, the absence of ANCA does not exclude the diagnosis of GPA. Among GPA patients with ANCA, 80-90% have PR3-ANCA.
In Churg-Strauss syndrome, what % of patients are ANCA positive? And what type of ANCA do they have?
~50% of CSS patients overall are ANCA positive, with the percentage being somewhat higher in those with active, untreated disease. There appears to be a moderate predilection for MPO-ANCA among those patients with CSS who have ANCA.
In microscopic polyangiitis, what % of patients are ANCA positive? And what type of ANCA do they have?
~70% of patients with MPA are ANCA positive. Most ANCA-positive MPA patients have MPO-ANCA.
~90% of patients with active generalized granulomatosis with polyangiitis (GPA) (Wegener’s granulomatosis) are ANCA-positive, and ~70% of patients with microscopic polyangiitis are ANCA positive. Can the type of ANCA (PR3-ANCA/c-ANCA or MPO-ANCA/p-ANCA) distinguish the 2 diseases?
Among GPA patients with ANCA, 80-90% have PR3-ANCA. This is in contrast to microscopic polyangiitis, where the majority of patients have MPO-ANCA. But, the 2 diseases cannot be distinguished based on ANCA specificity.
A negative ANCA assay does not rule out a vasculitis. On the other hand, elevated ANCA titers (often p-ANCA and generally low titer levels) have also been reported in many inflammatory conditions such as ___. ANCA positivity is seen in __% of patients with UC and PSC, and in __% of patients with Crohn’s disease.
A negative ANCA assay does not rule out a vasculitis. On the other hand, elevated ANCA titers (often p-ANCA and generally low titer levels) have also been reported in many inflammatory conditions such as RA, SLE, Sjogren’s syndrome, scleroderma and antiphospholipid syndrome. ANCA positivity is seen in 60-80% of patients with UC and PSC, and in 10-30% of patients with Crohn’s disease. Elevated ANCA titers can also be found in some healthy individuals.
What are some extrahepatic manifestations of HCV infection?
Hematologic diseases such as essential mixed cryoglobulinemia, lymphoma, and aplastic anemia. Renal disease, particularly membranoproliferative glomerulonephritis. Autoimmune disorders such as thyroiditis and the presence of autoantibodies. Dermatologic conditions such as porphyria cutanea tarda and lichen planus. Diabetes mellitus.
The classic ch-Aldrich syndrome phenotype includes what 3 characteristics?
Thrombocytopenia. Eczema. Recurrent bacterial, viral, and fungal infections (susceptibility to infections associated with adaptive and innate immune deficiency).
In Hashimoto’s disease, __% have anti-thyroglobulin Ab and __% have anti-thyroid peroxidase Ab. In Graves disease, __% have anti-thyroglobulin Ab and __% have anti-thyroid peroxidase Ab.
In Hashimoto’s disease, 90% have anti-thyroglobulin Ab and 95% have anti-thyroid peroxidase Ab. In Graves disease, 50% have anti-thyroglobulin Ab and 90% have anti-thyroid peroxidase Ab.
When can anti-insulin antibodies be seen?
Anti-insulin Abs can be raised in response to exogenous insulin, but this is rare in the era of human (recombinant?) insulin administration. Anti-insulin Abs may rarely occur in patients never exposed to exogenous insulin, and may cause reactive hypoglycemia (autoimmune insulin syndrome). Also, anti-insulin Abs may be found rarely in patients with insulinoma.
Do anti-insulin receptor antibodies cause hypoglycemia or hyperglycemia?
Hyperglycemia more commonly than hypoglycemia.
List causes of hypoglycemia.
Insulinoma. Nesidioblastosis. ILGF-like hormone secreting tumors (sarcomas, HCC). Advanced malignancy. Anti-insulin receptor antibodies. Autoimmune insulin syndrome. Post-gastric surgery. Drug induced (insulin, sulfonylureas, alcohol, quinine, salicylates, haloperidol, beta blockers, quinolones, pentamidine, ACE inhibitors, IGF-1). Critical illness such as hepatic/renal/cardiac failure, sepsis, inanition (def: an exhausted condition resulting from lack of food and water or a defect in assimilation; starvation). Hormone deficiency (cortisol, glucagon and epinephrine in insulin-deficient DM). Inborn errors of metabolism (glycogen storage disease, hereditary fructose intolerance, galactosemia, carnitine deficiency). Starvation. Accidental, surreptitious, or malicious hypoglycemia.
Autoantibodies can be frequently detected in type 1 diabetes. What are some targets?
Insulin. Islet cells. Glutamic acid decarboxylase (GAD65). ZnT8 (zinc transporter of islet beta cells). Insulinoma-associated protein 2 (IA-2 and IA-2 beta).
A single immunoglobulin molecule consists of 4 chains bound together by disulfide bonds: 2 heavy chains and 2 light chains. How many domains do the light chains and heavy chains have?
Light chains have 2 domains: 1 variable and 1 constant. Heavy chains have 4 to 5 domains: 1 variable and 3 to 4 constants. The terminal constant region may insert into the membrane of B cells, or, if free in serum, is called the Fc portion.
Genes for light chains are found on chromosome __ and __. Genes for heavy chains are found on chromosome __.
Genes for light chains are found on chromosome 2 (kappa) and 22 (lambda). Genes for heavy chains are found on chromosome 14 (gamma, alpha, mu, delta, eta).
There are 5 Ig classes based on the heavy chain isotype: IgG, IgA, IgM, IgD, and IgE. Which ones have subclasses, and what are they?
IgG has 4 subclasses: IgG1, IgG2, IgG3, IgG4. IgA has 2 subclasses: IgA1, IgA2.
There are 4 subclasses of IgG: IgG1, IgG2, IgG3, IgG4. Which one cannot cross the placenta? Which one cannot activate complement?
IgG2 cannot cross the placenta. IgG4 cannot activate complement.
There are 5 Ig classes based on the heavy chain isotype: IgG, IgA, IgM, IgD, and IgE. In what forms are they found in blood?
IgG - monomers (2 binding sites). IgA - dimers (4 binding sites). IgM - pentamers (10 binding sites). IgD - bound to B cells. IgE - bound to mast cells.
There are 5 Ig classes based on the heavy chain isotype: IgG, IgA, IgM, IgD, and IgE. Which ones can activate complement, and which pathway?
IgG and IgM activate the classical pathway. IgA activates the alternate pathway. IgD and IgE cannot activate complement.
There are 5 Ig classes based on the heavy chain isotype: IgG, IgA, IgM, IgD, and IgE. What immunopathogenic reactions do each produce?
IgG - immune complex (type III). IgA - immune complex, rarely. IgM - cytotoxic (type II). IgD - none. IgE - immediate-type hypersensitivity/allergic (type I).
T helper cells, T suppressor cells, and T cytotoxic cells. Which bear CD4, and which bear CD8?
T helper cells bear CD4. T suppressor cells and T cytotoxic cells bear CD8.
CD4+ T helper cells and CD8+ cytotoxic cells. Which is class I MHC restricted, and which is class II MHC restricted?
CD4+ helper cells must be presented antigen in conjunction with class II MHC molecules (they are class II MHC restricted). CD8+ cytotoxic cells must be presented antigen in conjunction with class I MHC molecules (they are class I MHC restricted).
Like immunoglobulins, T cell receptors get the variability in the variable domains from the randomness built into the rearrangement of the V, D, aand J segments of the variable region gene. But there is an additional degree of variability created by what enzyme?
There is an additional degree of variability created by the terminal deoxynucleotidyl transferase (TDT) enzyme which randomly adds nucleotides into the gene.
Over 95% of T cells have TCR alpha-beta. A small percentage of TCRs composed of gamma and delta subunits. These are found in greatest number in what body locations?
Mucosal surfaces and skin.
T cell receptors are expressed in noncovalent association with the CD__ molecule, which assists with transmembrane signaling when an antigen binds to the TCR.
T cell receptors are expressed in noncovalent association with the CD3 molecule, which assists with transmembrane signaling when an antigen binds to the TCR.
NK cells represent about 10% of peripheral blood lymphocytes. They are a subset of lymphocytic cells that bear neither the TCR or Ig; their TCR and Ig genes are in the germline (nonrearranged) state. NK cells express CD16, CD56, and CD57. What is CD16 the receptor for?
CD16 is the receptor for the Fc portion of gamma heavy chains. Through binding of opsonized cells with this receptor, they mediate antigen-dependent cellular cytotoxicity (ADCC); through this mechanism they are instrumental in combating viral infection and tumor cells.
All antigen presenting cells share phagocytic properties and certain cell antigens, such as what?
MHC class II antigens, CD68 (KP-1), and lysozyme. Antigens that are internalized by phagocytosis are processed and presented on the cell surface in association with MHC molecules. T cell stimulation and therefore stimulation of the remaining immune system begins with this. APCs also secrete IL-1.
IL-5, secreted by T cells, specifically stimulates the terminal differentiation release of eosinophils. A sub-subset of CD4+ T cells called Th2 cells stimulates both the production of IgE (secrete IL-__) and eosinophilic infiltration (secrete IL-5), particularly in the setting of parasitic infections.
IL-5, secreted by T cells, specifically stimulates the terminal differentiation release of eosinophils. A sub-subset of CD4+ T cells called Th2 cells stimulates both the production of IgE (secrete IL-4) and eosinophilic infiltration (secrete IL-5), particularly in the setting of parasitic infections.
What is the C3 convertase of the classic complement pathway and alternative complement pathway? What is the C5 convertase of the classic complement pathway and alternative complement pathway?
C3 convertase of the classic complement pathway = C4b2b. C3 convertase of the alternative complement pathway = C3bBb. C5 convertase of the classic complement pathway = C4b2b3b. C5 convertase of the alternative complement pathway = C3bBb3b.
All 3 pathways of complement activation (classical, alternative, and lectin pathways) result in the formation of activated C3b, which go on to form C5 convertases. What components produce the complement pathway effects of inflammation, opsonization, and membrane attack?
C3a and C5a (and C4a?) are anaphylatoxins, causing increased vascular permeability and promoting vasodilation and chemotaxis. C3b and C4b are opsonins. C5b6789 forms the membrane attack complex.
What is the “C3 tick over” phenomenon?
A small amount of autoactivated C3 is always present (so-called “C3 tick over” termed C3i or C3(H2O)) due to the presence of a labile thioester bond. C3 tick over is a mechanism by which the complement system monitors and probes the environment. The process is rapidly stopped on healthy human cells, but amplification may occur on foreign or damaged cells. The alternative pathway is engaged when this activated C3 binds factor B.
Human leukocyte antigen proteins are encoded by genes located within the major histocompatibility complex. The MHC complex is separated into MHC class I, class II, and class III genes which are located sequentially on chromosome ___. Also embedded in the MHC region are the genes for hereditary hemochromatosis, 21-hydroxylase, and tumor necrosis factor. These and the MHC genes are such closely linked loci that they are inherited en bloc from each parent, with no crossing over.
Human leukocyte antigen proteins are encoded by genes located within the major histocompatibility complex. The MHC complex is separated into MHC class I, class II, and class III genes which are located sequentially on chromosome 6p. Also embedded in the MHC region are the genes for hereditary hemochromatosis, 21-hydroxylase, and tumor necrosis factor. These and the MHC genes are such closely linked loci that they are inherited en bloc from each parent, with no crossing over.
On what cells are MHC class I and class II antigens expressed?
Class I antigens are found on nearly all nucleated cells and platelets (minimal to absent expression on RBCs). Class II antigens are found on macrophages, B cells, and activated T cells.
HLAs corresponding to MHC class I (__, __, and __) present peptides from inside the cell (including viral peptides if present). HLAs corresponding to MHC class II (__, __, __, __, __, and __) present antigens from outside of the cell to T-lymphocytes. HLAs corresponding to MHC class III encode components of the complement system.
HLAs corresponding to MHC class I (A, B, and C) present peptides from inside the cell (including viral peptides if present). HLAs corresponding to MHC class II (DP, DQ, DR, DM, DOA, and DOB) present antigens from outside of the cell to T-lymphocytes. HLAs corresponding to MHC class III encode components of the complement system.
What are the 3 major and 3 minor MHC class I genes in HLA? What protein binds with major and minor gene subunits to produce a heterodimer?
The 3 major genes: HLA-A, HLA-B, HLA-C. The 3 minor genes: HLA-E, HLA-F, HLA-G. Beta2-microglobulin binds with major and minor gene subunits to produce a heterodimer.
Describe HLA nomenclature.
Modern HLA alleles are typically noted with a variety of levels of detail. Most designations begin with HLA- and the locus name, then * and some (even) number of digits specifying the allele. The first two digits specify a group of alleles. Older typing methodologies often could not completely distinguish alleles and so stopped at this level. The third through fourth digits specify a synonymous allele. Digits five through six denote any synonymous mutations within the coding frame of the gene. The seventh and eighth digits distinguish mutations outside the coding region. Letters such as L, N, Q, or S may follow an allele’s designation to specify an expression level or other non-genomic data known about it. Thus, a completely described allele may be up to 9 digits long, not including the HLA-prefix and locus notation.
Since each MHC complex is closely linked and inherited en bloc, each parental chromosome can be thought of as a haplotype. Thus, the chance that 2 siblings are HLA-identical is essentially __%.
Since each MHC complex is closely linked and inherited en bloc, each parental chromosome can be thought of as a haplotype. Thus, the chance that 2 siblings are HLA-identical is essentially 25%. The chance of having an HLA-identical sibling goes up with the number of siblings: with 1 sibling, the chance is 25%, with 2 it is around 45%, and with 3 it is nearly 60%.
For deficiencies in B cells/immunoglobulins, T cells, phagocytes, and terminal complement, what types of infections are seen?
B cells/immunoglobulins - recurrent bacterial infections. T cells - viral and fungal infections. Phagocytes - Staphylococci. Terminal complement - encapsulated organisms (such as S. pneumoniae or N. meningitidis).
Is an absolute lymphopenia more common in B cell immune defects or T cell immune defects?
Absolute lymphopenia is uncommon in B defects but common in T cell defects.
What role does HLA testing have in the evaluation of immunodeficiency?
HLA testing does not normally have a role in the evaluation of immunodeficiency. It may be undertaken in other scenarios: pre transplantation compatibility testing, platelet refractoriness, paternity/forensic identity testing, and the evaluation of several HLA-linked autoimmune disorders.
What is the microlymphocytotoxicity assay?
The test detects either HLA antigens or antibodies. For Ag typing, it is best at detecting class I Ags (another technique, especially a DNA-based method, is preferred for detecting class II). For detecting Ags, HLA antisera are incubated with pt lymphocytes enriched from peripheral blood in the presence of excess complement, followed by the addition of dye. Microscopic examination shows either intact lymphs (a negative reaction) or damaged lymphs that internalize the dye (a positive reaction). For detecting Abs, pt serum is incubated with lymphs of known HLA type, and a similar procedure is carried out. The pt’s serum can be run against a panel of known lymph to determine the panel reactive antibody (PRA) level.
What is the mixed lymphocyte culture assay?
This test detects HLA class I (HLA-D) differences between a potential donor and recipient. After a B cell enrichment step (since class II molecules are numerous on B cells but not resting T cells), prospective donor and recipient B cells are cultured together. They proliferate if stimulated by one another’s HLA dissimilarities. At the end of the incubation period, the assay is pulsed with radioactive thymidine to determine the extent of DNA synthesis, a reflection of the amount of proliferation and thus the amount of incompatibility. By first subjecting the donor lymphocytes to irradiation (rendering them incapable of proliferation), the reaction can be made more specific for recipient intolerance of the potential donor.
In organ transplantation, ABO compatibility is most important, followed by HLA class ___ compatibility.
In organ transplantation, ABO compatibility is most important, followed by HLA class II compatibility.
Evaluation of HLA by serology vs. direct DNA testing (PCR).
PCR has the advantage of eliminating many of the biologic uncertainties of the serologic techniques such as microlymphocytotoxicity and mixed lymphocyte culture assays. Furthermore, it can resolve HLA types with much greater specificity than the serologic techniques. The DNA is usually obtained from peripheral blood.
What PCR techniques can be used for HLA typing?
Primers can be used that either amplify the locus of interest (regardless of its allele) for additional study; alternatively, primers may be used that will amplify the locus only if a specific allele is present - if a band results from this latter amplification, then that genotype is confirmed. In the former amplification, sequence-specific oligonucleotides can be applied to the amplified DNA to determine the identity of the alleles. For example, if looking for HLA-B27, the pt’s HLA-B locus can first be nonspecifically amplified then treated with HLA-B27-specific oligonucleotide probe to see if hybridization occurs. Alternatively, HLA-B27-specific primer sequences can be used in the amplification step; the presence of an identifiable band after PCR confirms HLA-B27. Also, an unknown allele can be directly sequenced and compared to known sequences.
HLA matching for transplantation usually involves at least what 3 loci?
HLA-A, HLA-B, and HLA-DR.
In HLA matching for transplantation, why is an in vitro assessment of compatibility (a crossmatch) still necessary when there appears to be a perfect 6 of 6 match?
HLA matching for transplantation usually involves at least 3 loci: HLA-A, HLA-B, and HLA-DR. Since each person has 2 alleles (one on each 6p) for each locus, there are 6 possible alleles. The potential recipient may have been sensitized to these and other not-normally-tested alleles through pregnancy or transfusion, so a crossmatch is still necessary. The lymphocyte crossmatch can detect pre-existing HLA allo-antibodies in the serum of the potential recipient that have specificity for HLA antigens in the potential donor. These HLA antibodies are the mediators of hyper acute rejection.
Transplantation crossmatch is usually performed by incubating donor (lymphocytes/serum) with recipient (lymphocytes/serum) in the presence of excess complement.
Transplantation crossmatch is usually performed by incubating donor lymphocytes with recipient serum in the presence of excess complement. An auto-crossmatch is performed to control for auto-antibodies (which do not appear to impact transplant survival).
For (organ) transplantation, one seeks ABO-compatible, HLA-matched (6 of 6 ideally), and crossmatch-compatible donor and recipient. Similar requirements are made for (organ) and (organ) transplants. For other organs, such as (organ) and (organ), such stringency is not required, and ABO-compatibility is the main concern.
For renal transplantation, one seeks ABO-compatible, HLA-matched (6 of 6 ideally), and crossmatch-compatible donor and recipient. Similar requirements are made for marrow and progenitor cell transplants. For other organs, such as heart and lung, such stringency is not required, and ABO-compatibility is the main concern.
A poor reaction (weak response to/low antibody titers developing against antigen) to carbohydrate antigens (such as pneumococcal vaccine, meningococcal vaccine, or ABO antigens), indicates a purely (B cell/T cell) defect.
A poor reaction (weak response to/low antibody titers developing against antigen) to carbohydrate antigens (such as pneumococcal vaccine, meningococcal vaccine, or ABO antigens), indicates a purely B cell defect. Antibodies raised to protein antigens require orchestration of B cell and T cell function.
What conditions are associated with high IgE levels?
Parasitic infection. Churg-Strauss syndrome. Hyper-IgE (Job) syndrome. IgE myeloma. Hodgkin lymphoma. IgE is not uniformly elevated in allergic states so is not a useful screening test in that setting.
The RAST (radio-allergosorbent test) is an allergen-specific IgE measurement that can be useful to evaluate allergy, principally for inhaled allergens. How is it performed?
RAST is used to determine levels of specific serum IgE antibodies by adding serum to a particular antigen, such as ragweed, complexed to a solid phase, followed by the addition of radiolabelled anti-IgE antibody. RAST is not a screening test because specified suspected antigens must be identified.
How useful is the RAST (radio-allergosorbent test) in evaluating hereditary angioedema (angioedema without urticaria) and chronic urticaria?
RAST is used to determine levels of specific serum IgE antibodies by adding serum to a particular antigen, such as ragweed, complexed to a solid phase, followed by the addition of radiolabelled anti-IgE antibody. These 2 conditions are not true IgE mediated allergic reactions, so RAST is not useful in these scenarios.
A proliferation assay can be performed to test T cell function. How is it performed?
T cells are exposed to mitogen, such as phytohemagglutinin or concanavalin A. Alternatively, the T cells can be exposed to cytokines such as IL-2, and the T cells proliferate in a cytokine concentration-dependent manner. Proliferation is measured by the uptake of radioactive DNA precursors (tritiated thymidine).
What is the chromium release assay used for?
To test NK cell function. Several laboratory methods exist for determining the efficacy of antibodies or effector cells in eliciting antibody dependent cell mediated cytotoxicity (classical ADCC is mediated by NK cells, but macrophages, neutrophils, and eosinophils can also mediate ADCC). Some of these methods include chromium-51 [Cr51] release assay, europium [Eu] release assay, and sulfur-35 [S35] release assay. Although the chromium release assay is considered the gold standard test for assessing NK cell activity, flow cytometric assays for the clinical measurement of NK cell activity have also been developed.
What is the best assay for testing neutrophil function?
An excellent screening test for neutrophils is simply the neutrophil count and peripheral smear, since most inherited defects in this arm of the immune system have readily identifiable numerical and/or morphologic findings. Also, myeloperoxidase staining can show myeloperoxidase deficiency, an AR trait which produces at most a mild immunodeficiency. But additionally, one can specifically look at chemotaxis, phagocytosis, and oxidative burst functions with various assays.
What test is used to screen for chronic granulomatous disease?
The nitroblue tetrazolium test.
What is the nitroblue-tetrazolium test?
It is a test used to screen for chronic granulomatous disease. Yellow NBT dye is added to neutrophils which are then stimulated. Cells capable of a normal oxidative burst will reduce the yellow NBT to a purple-blue formazan precipitate, and are said to be f+. Normal individuals will have nearly 100% f+ cells. An abnormal result, with perhaps less than 10% f+ dlls, is expected in CGD, in which deficiency of NADPH oxidase prevents the oxidative burst.
What specific complement components are low in the following diseases: lupus, membranoproliferative glomerulonephritis, terminal complement deficiency, properdin deficiency, C1-inhibitor deficiency/hereditary angioedema?
SLE causes low C3 and C4. MPGN causes low C3, but normal C4. Terminal complement deficiency is an inherited autosomal co-dominant condition with low C5, C6, C7, C8, C9 levels that causes susceptibility to infections by Neisseria. Properdin deficiency is an X-linked disorder that also causes susceptibility to neisserial infections. C1-inhibitor deficiency/hereditary angioedema will have low C4 with normal C1 and C3 levels.
What is the screening test for deficiencies in the complement pathway?
Total complement activity (CH50, sometimes called CH100) looks at the integrity of the entire classical complement pathway. This test measures what % of Ig-coated sheep RBCs are lysed by the pt’s serum. Quantitative deficiencies of any of the complement components C1-C9 will lead to a reduced CH50. Assays for quantitation of specific complement components are available as well.
Defective B cell function often presents after 6 mos of age, due to persistence of maternal Abs in the infant serum. What are characteristic infections?
Recurrent bacterial sinopulmonary infections due to staphylococci, streptococci, and hemophilus. Also, recalcitrant intestinal infection with G. lamblia. Opportunistic fungal and viral infections are not a particular problem.
Bruton (X-linked) agammaglobulinemia. What are characteristic histologic and lab findings?
Absence of plasma cells in lamina propria of intestinal mucosa. Lymph nodes lack germinal centers, and plasma cells are absent. Tonsils are rudimentary. Serum IgG levels are markedly reduced as are circulating mature B cells. Pre-B cells are found in lymph nodes and bone marrow where they do not mature normally into B cells.
Patient’s with Bruton (X-linked) agammaglobulinemia have normal immunity against most viral and fungal pathogens, but they do show susceptibility to what 3 viruses?
Polio, hepatitis, and enteroviruses.
Bruton (X-linked) agammaglobulinemia is due to mutation in what gene?
A gene on the X chromosome encoding a tyrosine kinase called Atk (agammaglobulinemia tyrosine kinase) or Btk (Bruton’s tyrosine kinase).
What is common variable immunodeficiency?
CVID is a group of approximately 150 primary immunodeficiencies characterized by hypogammaglobulinemia (low IgG, IgA, and IgM) but which have different underlying causes. In CVID, the B cells are normal in numbers but they lack the capacity to differentiate into plasma cells, so the pts do not make an effective amount of Ig. The clinical severity and age of onset are somewhat variable; the typical onset is around the 2nd or 3rd decade.
In common variable immunodeficiency, B cells are normal in numbers in blood and tissue but they lack the capacity to differentiate into plasma cells, so the pts do not make an effective amount of Ig. What are characteristic histologic features?
Germinal centers are hyperplastic; the typical small bowel morphology includes pronounced reactive follicular lymphoid hyperplasia in the face of a distinctly low number of plasma cells.
What common infections are seen in common variable immunodeficiency?
Most pts suffer from recurrent upper and lower respiratory tract infections (S. pneumonia, H. influenza, and Mycoplasma), intestinal bacterial overgrowth, and intestinal G. lamblia infection. The development of bronchiectasis is extremely common.
Selective IgA deficiency is the most common inherited immunodeficiency, affecting around 1 in ___ people. What conditions are they susceptible to?
Selective IgA deficiency is the most common inherited immunodeficiency, affecting around 1 in 700 people. They are susceptible to recurrent respiratory and GI bacterial infections, a high incidence of autoimmunity, and are at risk for anaphylaxis due to transfusion of IgA-containing blood products.
Job (hypergammaglobulinemia E) syndrome presents with abnormally high serum IgE. What conditions are they susceptible to?
They have high levels of specific IgE anti-staphylococcal antibody, exquisite susceptibility to staphylococcal infection, eosinophilia and eczema. These appear to result from a defect in granulocyte chemotaxis.
How is the CATCH-22 mnemonic used to describe DiGeorge syndrome?
Salient clinical features are described by the CATCH: Cardiac abnormality (especially tetralogy of Fallot), Abnormal facies, Thymic aplasia, Cleft palate, Hypocalcemia/Hypoparathyroidism. The 22 refers to the deletion of 22q11.2 that causes DiGeorge syndrome.
The vast majority of cases of DiGeorge syndrome are caused by deletions at what chromosome locus?
What is type II DiGeorge syndrome?
A small number of patients with the phenotypic features of DiGeorge syndrome have deletions on 10p13-p14 (DiGeorge syndrome II locus) instead of at the 22q11.2 locus typical of DiGeorge syndrome. But this is now thought to be a separate entity from DiGeorge syndrome.
DiGeorge syndrome has failure of development of which pharyngeal pouches?
Third and fourth.
What inheritance pattern does SCID show?
50% are X-linked and due to a defect in the IL-2 receptor. 40% are autosomal recessive and due to deficiency in the enzyme adenosine deaminase. The remainder are also autosomal recessive and due to numerous defects such as in JAK3, CD45, IL7R, TCR, PNP, RAG1, RAG2, STAT5a, ZAP-70, and many others.
The gene responsible for Wiskott-Aldrich syndrome is the WAS gene on the X chromosome. The product of the gene is the WASP (Wiskott-Aldrich syndrome protein). What is the function of this protein?
WASP is found mainly within hematopoietic cells and appears to be responsible for the cytoskeletal malleability that is necessary for physiologic activities.
Is the immunodeficiency in Wiskott-Aldrich syndrome due to defects in T cells, B cells, or both?
What infections are patients with Wiskott-Aldrich syndrome susceptible to?
Pneumococci and other encapsulated bacteria, Pneumocystic carinii, and herpes virus. They also have a 12% incidence of fatal malignancies.
What is Louis-Bar syndrome?
Ataxia-telangiectasia, AKA Louis-Bar syndrome, is due to a mutation in what gene on what chromosome?
The ATM (Ataxia-telangiectasia Mutated) gene on 11q22.3.
Ataxia-telangiectasia is an autosomal recessive disorder caused by mutations in the ATM (Ataxia-telangiectasia Mutated) gene on 11q22.3. What protein does this gene encode, and what is its function?
The gene encodes the ATM protein kinase, which is involved in DNA repair.
Individuals with ataxia-telangiectasia have very high serum levels of ___ and ___ for unknown reasons.
Individuals with ataxia-telangiectasia have very high serum levels of AFP and CEA for unknown reasons.
What is the lifetime risk of malignancy for patients with ataxia-telangiectasia?
38%, and hematolymphoid malignancies account for most of these.
How can ataxia-telangiectasia be diagnosed?
Immunoblotting assay for the ATM protein in nuclear lysate ~90% have no ATM, ~10% have trace amounts, and ~1% have a normal amount of protein that lacks ATM serine/threonine kinase activity). Assays for ATM kinase activity (uses immunoblotting of cell lysates and commercial antibodies to many phosphorylated ATM target substrates). Radiosensitivity assay (determines the survival of patient lymphoid cells following irradiation, and this is abnormal in more than 95% of affected individuals). A t(7;14) is found in 5-15% of cells in peripheral blood chromosome studies in affected individuals. Sequence analysis of the ATM coding region detects about 90% of ATM sequence variants.
Chronic mucocutaneous candidiasis is a highly selective defect in (B cell and/or T cell?) immunity to candidal infection that leads to chronic, recalcitrant, mucocutaneous candidal infection. Affected individuals often have associated endocrinopathies.
Chronic mucocutaneous candidiasis is a highly selective defect in T cell immunity to candidal infection that leads to chronic, recalcitrant, mucocutaneous candidal infection. Affected individuals often have associated endocrinopathies.
How does Duncan disease (X-linked lymphoproliferative disease) typically present?
Typically as a fulminant and often fatal immune response to EBV infection. EBV infection induces a fulminant hemophagocytic syndrome, the development of a neoplastic B cell proliferation, and/or fulminant hepatic failure, concomitant with an inverted CD4:CD8 ratio in the peripheral blood.
Duncan disease (X-linked lymphoproliferative disease) typically presents as a fulminant and often fatal immune response to EBV infection. Even before EBV infection, what defects are seen?
Affected individuals often have a common variable immunodeficiency-like immune system defect, especially manifesting hypogammaglobulinemia with or without decreased B, T, or NK subsets. The median survival is about 10 years of age.
Duncan disease (X-linked lymphoproliferative disease) can be caused by mutations in either of what 2 genes?
SH2D1A, which encodes for SH2 domain protein-containing protein 1A/SLAM-associated protein (SAP). XIAP (also known as BIRC4), which encodes for baculoviral IAP repeat-containing protein 4 (X-linked inhibitor of apoptosis; XIAP), respectively. The former is sometimes referred to as XLP1, and the latter XLP2.
Duncan disease (X-linked lymphoproliferative disease) can be caused by mutations in either SH2D1A, which encodes for SH2 domain protein-containing protein 1A/SLAM-associated protein (SAP), or by mutations in XIAP (also known as BIRC4), which encodes for baculoviral IAP repeat-containing protein 4 (X-linked inhibitor of apoptosis; XIAP). What are the %s of XLP caused by each mutation?
SH2D1A: 83-97%. XIAP: 12%.
How is Duncan disease (X-linked lymphoproliferative disease) diagnosed?
Molecular testing (sequence analysis or deletion/duplication analysis) for one of the causative genes: SH3D1A or XIAP. Also, SAP and XIAP protein expression by flow cytometry may be used as a screening test prior to molecular genetic testing of the SH2D1A or XIAP genes.
Defects in phagocytosis lead to particular susceptibility to infections with what organisms?
Staphylococci, E. coli, S. pneumoniae, P. aeruginosa, C. albicans.
Mutations in what genes cause chronic granulomatous disease?
CGD is caused by mutation of one of five genes that encode the subunits of phagocyte NADPH oxidase: biallelic mutations in CYBA, NCF1, NCF2, and NCF4 cause autosomal recessive CGD; mutation of CYBB causes X-linked CGD.
How common is infection with Streptococci in patients with chronic granulomatous disease?
Is it almost never seen. CGD is characterized by chronic suppurative infections due to bacteria and fungi that are catalase positive, especially Staphylococci, Enterobacter, and Aspergillus.
Chediak-Higashi syndrome is an [mode of inheritance] condition that presents as neutropenia, recurrent infection, thrombocytopenia, and oculocutaneous albinism. Granulocytes, lymphocytes, and monocytes show giant cytoplasmic granules, representing ___. The basic abnormality is ___. In late stages, an accelerated phase may develop, characterized by ___.
Chediak-Higashi syndrome is an autosomal recessive condition that presents as neutropenia, recurrent infection, thrombocytopenia, and oculocutaneous albinism. Granulocytes, lymphocytes, and monocytes show giant cytoplasmic granules, representing abnormally fused lysosomes. The basic abnormality is defective degranulation. In late stages, an accelerated phase may develop, characterized by lymphoma-like proliferations within viscera.
Integrin deficiencies, due to deficiencies of the integrins LFA-1 or MAC-1, characteristically manifest as ___ and ___.
Integrin deficiencies, due to deficiencies of the integrins LFA-1 or MAC-1, characteristically manifest as periodontitis and delayed cord separation.
May-Hegglin anomaly is an [mode of inheritance] condition manifesting as Dohle-like bodies in granulocytes and monocytes, large platelets, and thrombocytopenia. The Dohle-like bodies can be abolished by the addition of ___. __% of patients have an abnormal bleeding history, but bleeding complications have only been documented when the platelet count falls below 80,000. Platelet aggregation studies are usually normal, and there does not appear to be much of an immune defect.
May-Hegglin anomaly is an autosomal dominant condition manifesting as Dohle-like bodies in granulocytes and monocytes, large platelets, and thrombocytopenia. The Dohle-like bodies can be abolished by the addition of ribonuclease. 50% of patients have an abnormal bleeding history, but bleeding complications have only been documented when the platelet count falls below 80,000. Platelet aggregation studies are usually normal, and there does not appear to be much of an immune defect.
Alder-Reilly anomaly is mainly a morphologic finding. It is an [mode of inheritance] condition manifesting as large azurophilic granules resembling toxic granulation in all white blood cells. There is an association with [storage disorder].
Alder-Reilly anomaly is mainly a morphologic finding. It is an autosomal dominant condition manifesting as large azurophilic granules resembling toxic granulation in all white blood cells. There is an association with mucopolysaccharidoses.
Pelger-Huet anomaly is an [mode of inheritance] disorder with dysfunctional segmentation of neutrophils. Bilobed neutrophils are seen rather than normally segmented forms. In homozygotes, monolobated neutrophils (___ cells) are seen. Functionally, the cells are normal.
Pelger-Huet anomaly is an autosomal dominant disorder with dysfunctional segmentation of neutrophils. Bilobed neutrophils are seen rather than normally segmented forms. In homozygotes, monolobated neutrophils (Stodtmeister cells) are seen. Functionally, the cells are normal.
Deficiency of classical pathway components (C1q, C2, C4) lead to ___. Deficiency of C2 and C3 lead to ___. Deficiency of membrane attack complex components (C5-C9) leads to ___.
Deficiency of classical pathway components (C1q, C2, C4) lead to autoimmune phenomena such as lupus. Deficiency of C2 and C3 lead to recurrent infections with gram-positive encapsulated organisms. Deficiency of membrane attack complex components (C5-C9) leads to recurrent serious systemic infections, especially due to N. meningitidis and N. gonorrhea.
C1 esterase inhibitor (C1 Inh) deficiency is an autosomal dominant disorder also called hereditary angioedema. What parts of the body are affected?
Swelling is seen most consistently in the skin (upper extremity more than lower) and intestinal tract (abdominal pain episodes). Laryngeal edema, though classic and potentially lethal, is present in only about 1% of episodes but has a lifetime incidence of 50%. Facial swelling is rare, and while there is swelling of the soft palate and uvula, it spares the tongue. Acute episodes are treated with androgenic agents.
C1 esterase inhibitor (C1 Inh) deficiency is an autosomal dominant disorder also called hereditary angioedema. What are the 2 forms of HAE?
Type I (C1 Inh is absent). Type II (C1 Inh is present but functionally defective). A third type of HAE has been described that is not associated with C1-INH deficiency, and its underlying mechanism is unknown.
C1 esterase inhibitor (C1 Inh) deficiency is an autosomal dominant disorder also called hereditary angioedema. What changes in complement are seen during attacks and between attacks?
Urinary histamine levels and serum C1 levels are elevated during attacks, while serum CH50, C4, and C2 are decreased. Between attacks, C4 is always low, while C2 levels are normal.
What are the 2 main types of immunofluorescence tests for autoantibodies, and how are they performed?
Direct immunofluorescence (DIF) involves incubating cryostat sections of patient tissue with fluorescein-labeled AHG. Positive DIF tests confirm the in vivo presence of bound autoantibodies in the patient’s tissues. Examples include skin IF and renal IF. Indirect immunofluorescence (IIF) involves incubating patient serum with cells/tissue known to contain specific antigens, then adding fluorescein-labeled AHG. Positive IIF tests confirm the presence of circulating autoantibodies.
What is the procedure for screening for ANA using HEp-2 cells?
Incubate patient serum (diluted 1:40) with HEp-2 cells, add fluorescein-labeled AHG, and counterstain. Examine for presence and pattern of fluorescence. Serially dilute all positives to determine titer. Currently, EIA techniques are emerging that may supplant this traditional indirect immunofluorescence ANA test.
What do the patterns of fluorescence seen on ANA screening indicate positivity to? For each pattern, do mitoses show positive or negative staining?
Homogeneous/diffuse pattern: Represents antibodies to the DNA-histone complex, also called deoxyribonucleoprotein or nucleosome. Mitoses+. Peripheral/rim pattern: Represents antibodies to dsDNA and antibodies to nuclear envelope antigens, particularly to lamins. Mitoses+. Speckled pattern: Produced by antibodies to Sm, RNP, Ro/SSA, La/SSB, Scl-70, centromere, proliferating cell nuclear antigen (PCNA), and other antigens. Mitoses-. Nucleolar pattern: Produced by antibodies to RNA polymerase I, proteins of the small nucleolar RNP complex (“anti-nucleolar”). Mitoses-. Centromere pattern: Produced by antibodies to proteins that are associated with the site of chromosomal constriction (are only present on active centromeres ie, during mitosis and meiosis) (“anti-centromere”). Mitoses+.
What is the procedure for screening for antibodies to cytoplasmic constituents?
Incubate patient serum (diluted 1:40) with cryostat sections of tissue “sandwich” consisting of rat liver, kidney, and stomach (fundic mucosa and smooth muscle). Add fluorescein-labeled AHG. Add counterstain. Examine for fluorescence. Titer all positives.
In screening for antibodies to cytoplasmic constituents, sections of a tissue “sandwich” consisting of rat liver, kidney, and stomach are stained with fluorescein-labeled AHG. Staining in which cells indicates AMA+, ASMA+, APA+, and anti-LKM+?
AMA+ in gastric parietal cells, renal tubular cells, and hepatocytes. ASMA+ in gastric smooth muscle and renal parenchymal arteries. APA+ in gastric parietal cells. Anti-LKM+ in cytoplasm of hepatocytes and renal tubular cells.
What is the procedure for screening for ANCA?
Incubate patient serum with alcohol-fixed neutrophils. Add fluorescein-labeled AHG. Add counterstain. Examine for presence and type (cytoplasmic or perinuclear) fluorescence. Run ANA screen on all positives.
How can the presence of anti-dsDNA be detected?
Either by indirect immunofluorescence assay using the substrate Crithidia luciliae or by ELISA.
What is the procedure for detecting anti-thyroid antibodies?
Incubate serum with cryostat sections of thyroid. Add fluorescein-labeled AHG. Examine: Fluorescence that highlights follicular epithelial cell cytoplasm is anti-thyroid microsomal, while fluorescence that highlights follicular contents is anti-thyroglobulin.
What is the clinical utility of anti-nuclear antibody?
This test is nonspecific. Individuals are more likely to be ANA positive with age, with a 50% incidence rate by age 80, but this is usually low titer. The various patterns of immunofluorescence (homogeneous/diffuse, peripheral/rim, speckled, nucleolar, and centromere) have antibody specificities. The only 2 with good correlation are anti-nucleolar, which correlates with scleroderma, and anti-centromere, which correlates with the CREST variant of scleroderma.
What is the clinical utility of anti-dsDNA antibody?
AKA anti-nativeDNA. Has high specificity for SLE. The substrate, Crithidia luciliae, is a flagellate with a giant mitochondrion that contains dsDNA concentrated in the kinetoplast. Antibodies to ssDNA do not react with C. luciliae.
Do antibodies to ssDNA, dsDNA, or both react with Crithidia luciliae?
C. luciliae has dsDNA concentrated in the kinetoplast. Antibodies to dsDNA will react, while antibodies to ssDNA do not react.
The ANA test has a sensitivity of around __% for SLE.
The ANA test has a sensitivity of around 99% for SLE. A negative ANA virtually excludes active SLE. For specificity, both the pretest probability and the titer are important. When a cutoff titer of 1:40 is used, the specificity is 80%. When 1:160 is used, the specificity is 95%.
A large number of individuals with no disease (do not have SLE) or with unrelated diseases have a positive ANA. __% of normal individuals have an ANA titer of 1:40; __% have a titer as high as 1:160. In testing for SLE, when a cutoff titer of 1:40 is used, the specificity is __%; when 1:160 is used, the specificity is __%.
A large number of individuals with no disease (do not have SLE) or with unrelated diseases have a positive ANA. 20% of normal individuals have an ANA titer of 1:40; 5% have a titer as high as 1:160. In testing for SLE, when a cutoff titer of 1:40 is used, the specificity is 80%; when 1:160 is used, the specificity is 95%.
What are conditions associated with a positive ANA?
SLE, other autoimmune diseases (Sjogren syndrome, scleroderma, RA), multiple sclerosis, infections, malignancies, and fibromyalgia.
Once the ANA is found to be positive, additional testing can help confirm the diagnosis of SLE, particularly testing for what 3 antibodies?
Anti-dsDNA, anti-Sm, and anti-phospholipid.
What is the clinical utility of anti-Jo1 antibody?
Also called anti-tRNA synthetase. Implies high likelihood of developing interstitial lung disease in polymyositis/dermatomyositis.
What is the clinical utility of anti-histone antibody?
High specificity for drug-induced systemic lupus. Associated drugs include hydralazine, procainamide, isoniazid, dilantin, aldomet, and penicillin.
What is the clinical utility of the extractable nuclear antigens?
A number of antigens, the so-called ENAs, are present in the extract of calf thymus. ENAs typically give a speckled pattern on fluorescent ANA testing. ENAs include Smith, RNP, SS-A (Ro), and SS-B (La).
What is the clinical utility of anti-Smith (Sm) antibody?
Virtually diagnostic of SLE.
What is the clinical utility of anti-RNP antibody?
Suggests mixed connective tissue disease.
What is the clinical utility of anti-nucleolar antibody?
Correlates with scleroderma.
What is the clinical utility of anti-SS-A and anti-SS-B antibodies?
SS-A (Ro) is present in 70% of patients with Sjogren syndrome and 30% of patients with SLE. SS-B (La) is present in 50% of patients with Sjogren syndrome and 15% of patients with SLE. Anti-SS-A/SS-B are found in children with neonatal lupus. Patients who are ANA+, SS-A+ but SS-B neg are very likely to have lupus nephpritis.
What is the clinical utility of anti-mitochondrial antibody?
AMA is detected in 85% of patients with primary biliary cirrhosis.
What is the clinical utility of anti-smooth muscle antibody?
Lupoid (autoimmune) hepatitis is characterized by titers of greater than 1:80. ASMA are specifically directed at F-actin.
What is the clinical utility of anti-microsomal antibody AKA anti-thyroid microsomal antibody?
High specificity (90%) and sensitivity (95%) for Hashimoto disease, although up to 50% of patients with Graves disease will have antibodies. Note: Anti-liver kidney microsomal type 1 antibody is different, and is found in autoimmune hepatitis.
What is the clinical utility of anti-endomysial antibody?
Endomysin is present in the reticular investment of muscle fibers. Anti-endomysial antibodies are IgA antibodies. They are highly sensitive and specific for celiac sprue and dermatitis herpetiformis. Antibody titers respond to a gluten-free diet.
What is the clinical utility of cold agglutinin antibodies?
Cold agglutinins are IgM antibodies directed against I or i antigens on RBCs. In cold agglutinin disease, they are monoclonal IgM kappa antibodies. In infectious mono, they are anti-i antibodies. In Mycoplasma pneumonia, they are anti-I antibodies.
Mycoplasma pneumonia is associated with anti-I cold agglutinin. Titers are found in __% of infected individuals, peaking at __ to __ days.
Mycoplasma pneumonia is associated with anti-I cold agglutinin. Titers are found in 50% of infected individuals, peaking at 14 to 21 days.
What is the clinical utility of anti-centromere antibodies?
High specificity for CREST variant of scleroderma.
What is the clinical utility of anti-GBM antibodies?
Goodpasture syndrome; the epitope is the M2 subunit of type IV collagen.
What is the clinical utility of anti-IF antibodies?
IF = intermediate filament. Polymyositis/dermatomyositis.
What is the clinical utility of anti-Scl-70 antibodies?
Anti-Scl-70 antibody is an anti-topoisomerase Ig seen in 20% of patients of scleroderma.
What is the clinical utility of anti-PM1 antibodies?
Overlap syndrome with overlapping features of scleroderma and dermatomyositis.
What is the clinical utility of cANCA antibodies?
High specificity for Wegener syndrome; cANCA is anti-proteinase 3 (PR3).
What is the clinical utility of anti-thyroglobulin antibodies?
What is the clinical utility of anti-thyroid-stimulating antibodies?
Also called LATS, it is present in 90% of individuals with Graves disease.
What are the CDC criteria for interpreting an HIV Western blot as positive?
The presence of any two of the following bands is a positive result: p24, gp41, and gp120/160. Distinguishing the gp120 band from the gp 160 band is often very difficult, and these 2 glycoproteins can be considered as one reactant for purposes of interpreting WB test results.
For as HIV Western blot, the presence of any two of the following bands is a positive result: p24, gp41, and gp120/160. What is the function of each protein/glycoprotein?
p24 is capsid protein/viral core protein encoded by gag. gp41 is transmembrane envelope glycoprotein encoded by env. gp160 is viral envelope precursor encoded by env. gp120 is viral envelope protein that binds to CD4 encoded by env.
What is the clinical utility of rheumatoid factor?
RFs are IgM antibodies directed against the Fc fragment of IgG. RF may be “falsely” positive in a multitude of conditions including SBE, syphilis, infectious mononucleosis, and many rheumatologic diseases.
What is the clinical utility of anti-parietal cell antibodies?
80% sensitive for pernicious anemia, but only 70% specific. Presence of the APCA does not correlate with B12 malabsorption.
What is the clinical utility of anti-intrinsic factor antibodies?
50-75% sensitive for adult pernicious anemia, but 90% sensitive for pediatric pernicious anemia. There are 2 types: type I, blocking Ab, reacts only with unbound IF, and is extremely specific; type II, binding Ab, reacts with unbound and bound IF, and is both less specific and less sensitive than type I.
What is the clinical utility of cryoglobulin?
Cryoglobulins may be present in Waldenstrom macroglobulinemia, myeloma, CLL, SLE, CAH, and viral infections.
What are the frequencies of the following antibodies in SLE: dsDNA, Sm, RNP, SS-A (Ro), SS-B (La), histone?
dsDNA - 40%. Sm - 30%. RNP - 30%. SS-A (Ro) - 30%. SS-B (La) - 30%. Histone - 70%.
Anti-dsDNA and anti-Sm antibodies are essentially restricted to SLE. Increases in titers of which predicts flares in SLE?
Increases in anti-dsDNA Ab titers predict flares in SLE.
High-titered anti-RNP (greater than 1:10,000) is characteristic of what disease?
Mixed connective tissue disease, particularly if unaccompanied by other ANAs. Anti-RNP is commonly seen in SLE, but titers are usually modest.
Anti-Ro and anti-La with negative dsDNA and negative Sm is compatible with what disease?
Anti-Scl-70 (anti-topoisomerase I) is seen exclusively in what disease?
Progressive systemic sclerosis.
Anti-centromere antibody strongly suggests ___ and is occasionally seen in ___ and ___.
Anti-centromere antibody strongly suggests CREST syndrome and is occasionally seen in progressive systemic sclerosis and Raynaud syndrome.
Drug-induced lupus develops mostly in “slow acetylators” who are taking hydralazine, procainamide, or isoniazid. This form of lupus is usually negative for what 3 antibodies, but is characterized by what 2 antibodies?
Drug-induced lupus is usually negative for dsDNA, Sm, and RNP but is characterized by ANA and anti-histone antibodies directed at H2 (H2A and H2B) histone proteins.
Anti-mitochondrial antibodies are associated with primary biliary cirrhosis. What are they directed at specifically?
Anti-mitochondrial antibodies are directed against a mitochondrial antigen from the inner mitochondrial membrane, called M2, which is thought to be dihydrolipoamide acetyltransferase, a component of the pyruvate dehydrogenase enzyme complex.
Anti-M2 mitochondrial antibodies are found in about __% of patients with primary biliary cirrhosis. What is the specificity?
Anti-M2 mitochondrial antibodies are found in about 90% of patients with primary biliary cirrhosis. They are highly (95-99%) specific.
Antibodies to mitochondrial antigens M1 to M9 are associated with various diseases. List.
M1, M2, and M7 are on inner mitochondrial membranes, while M3, M4, M5, M6, M8, and M9 are on outer mitochondrial membranes. Anti-M1: syphilis. Anti-M2, anti-M4, anti-M8, anti-M9: primary biliary cirrhosis (anti-M2 is a specific marker for the diagnosis of PBC). Anti-M3: phenopyrazon-induced pseudolupus syndrome. Anti-M5: undefined collagen diseases. Anti-M6: iproniazid-induced hepatitis. Anti-M7: cardiomyopathy.
Anti-liver kidney microsomal type 1 antibody is associated with what condition?
LKM-1 autoantibodies are found in autoimmune hepatitis. Note: Anti-microsomal antibodies (or anti-thyroid microsomal antibodies) are different (a group of anti-thyroid antibodies, which were renamed after the identification of their target antigen, TPO; they have high specificity and sensitivity for Hashimoto disease).
Why is testing for ANA performed on all positive ANCA tests?
To exclude a false-positive ANCA due to the presence of ANAs.
c-ANCA has anti-___ specificity, while p-ANCA has predominantly anti-___ activity.
c-ANCA has anti-proteinase 3 (PR3) specificity, while p-ANCA has predominantly anti-myeloperoxidase (MPO) activity.
c-ANCA is positive in __% of Wegener granulomatosis. Does its presence correlates with activity? Specificity?
c-ANCA is positive in 90% of Wegener granulomatosis. Its presence does correlate with activity, and c-ANCA titers can be monitored to follow disease activity. It is highly (95-99%) specific for Wegener granulomatosis.
p-ANCA is less specific than c-ANCA but still has clinical utility, since it is seen in a small number of disorders. List.
Primary sclerosing cholangitis. Ulcerative colitis. Microscopic polyangiitis. Also, RA and Churg-Strauss syndrome.
The LE cell is a traditional marker of SLE. In tissue samples and body fluids, the LE cell is any phagocytic cell that has an engulfed denatured nucleus. How is the LE cell test performed? In what % of cases of SLE is the LE cell test positive?
The LE cell test is performed by agitating a test tube, thus damaging some nucleated cells whose liberated nuclei are then engulfed. A smear from this fluid is then examined for LE cells. The LE cell test is positive in 70% of cases of SLE.
ACE is an enzyme found in high concentrations in pulmonary endothelium. ACE levels are an extremely useful test in the evaluation of patients with what suspected granulomatous disease?
Sarcoidosis. ACE is nearly always elevated in active sarcoidosis. Inactive sarcoidosis is associated with normal levels of ACE.
Other than active sarcoidosis, what are other causes of elevated ACE?
Primary biliary cirrhosis, Gaucher disease, and leprosy. All of these have in common the formation of granulomas; however, most other granulomatous diseases are not associated with an elevated ACE.
What diseases are associated with the following HLA types: HLA-DR2, HLA-DR3, HLA-DR4, HLA-B27?
HLA-DR2: multiple sclerosis, narcolepsy, protective for IDDM. HLA-DR3: SLE, Sjogren syndrome, myasthenia gravis, Graves disease (The DR3-DQ2 linkage is associated with IDDM, dermatitis herpetiformis, and celiac disease). HLA-DR4: IDDM, RA, pemphigus vulgaris. HLA-B27: ankylosing spondylitis and other “reactive” arthritidies.
Autoimmune diseases are most prevalent in women of reproductive age. Notable exceptions are ___ and ___. Several diseases, most notably ___, are typically more severe when they affect males.
Autoimmune diseases are most prevalent in women of reproductive age. Notable exceptions are ankylosing spondylitis (males much more common than females) and Sjogren syndrome (postmenopausal females). Several diseases, most notably RA, are typically more severe when they affect males.
What autoimmune condition are each of the following triggering exposures correlated with: Coxsackie B virus infection; HBV infection; K. pneumoniae infection; aldomet; penicillamine; procainamide, hydralazine, and isoniazid.
Coxsackie B virus infection - development of IDDM. HBV infection - polyarteritis nodosum. K. pneumoniae infection - onset of ankylosing spondylitis. Aldomet - WAIHA. Penicillamine - systemic vasculitis. Procainamide, hydralazine, and isoniazid - drug-induced SLE.
What are hypersensitivity reactions? Who initially created with 4 group classification of hypersensitivities?
Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized (immune) state of the host. The four-group classification was expounded by P. G. H. Gell and Robin Coombs in 1963.
What are the 4 (plus one) types of hypersensitivity reactions, their mediators, and associated diseases?
Type I (allergic, immediate-type): IgE; atopy, asthma, anaphylaxis. Type II (antibody-dependent, cytotoxic, antibody-mediated cellular cytotoxicity): IgM or IgG, complement, MAC; Goodpasture syndrome, autoimmune hemolytic anemia, erythroblastosis fetalis, rheumatic heart disease (also Graves disease and myasthenia gravis, but some classify these as type V). Type III (immune complex): IgG, complement, neutrophils; SLE, serum sickness, Arthus reaction, PSGN. Type IV (delayed-type, cell-mediated immune memory response, antibody-independent): T cells; tuberculin skin test, contact dermatitis, MS. Type V (an additional subtype sometimes used as a distinction from type II) (receptor mediated autoimmune disease): IgM or IgG, complement; Graves disease, myasthenia gravis.
The mechanism of type I hypersensitivity reactions (immediate-type) is antigen binding to IgE on the surface of mast cells (bound by the FceR) leading to IgE crosslinking and resulting degranulation (histamine, heparin, serotonin, arachidonate). How are anaphylactoid reactions different?
Anaphylactoid reactions result from mast cell degranulation without IgE intermediation (heat, cold, trauma).
Pemphigus vulgaris, bullous pemphigoid, epidermolysis bullosa acquisita, dermatitis herpetiformis. All are autoimmune disorders, with the first resulting in suprabasal vesiculation and the other three resulting in subepithelial vesiculation. What is the antibody for each condition, how are they detected, and what is the pattern of reactivity?
Pemphigus vulgaris: anti-desmosomal; DIF on cryostat sections of skin results in chicken-wire IgG in epidermis. Bullous pemphigoid: anti-epithelial basement membrane/anti-hemidesmosome; DIF on cryostat sections of skin results in linear IgG along BM; in salt-split skin results in reactivity in roof. Epidermolysis bullosa acquisita: EBA Ag (? type VII collagen); DIF on cyrostat sections results in linear IgG along BM; in salt-split skin results in reactivity in floor. Dermatitis herpetiformis: gluten; DIF on cryostat sections of skin results in granular IgA especially in tips of dermal papillae.
Bullous pemphigoid and epidermolysis bullosa acquisita both show linear IgG along the BM in DIF performed on cryostat sections of skin. How can they be differentiated?
In salt-split skin, BP has reactivity in roof, while EBA has reactivity in floor.
Why is the specificity of IgA anti-transglutaminase antibodies for celiac sprue low in the setting of chronic liver disease?
There is a high incidence of IgA anti-transglutaminase antibodies in patients with chronic liver diseases (particularly among those with autoimmune liver diseases).
Anti-transglutaminase antibodies, anti-endomysial antibodies, and antigliadin antibodies vary with exposure to gluten, but none correlate with mucosal recovery in celiac disease. What test of mucosal absorption, and what serum analyte does correlate with mucosal recovery?
Tests of mucosal absorption, such as the D-xylose absorption test, may be useful. Transthyretin (a rapidly responsive indicator of nutritional status) correlates very well with mucosal recovery.
What auto-antibodies are associated with Hashimoto disease, and how are they detected?
Anti-microsomal and anti-thyroglobulin. IIF on cryostat sections of thyroid tissue; latex agglutination.
What auto-antibodies are associated with Graves disease, and how are they detected?
Anti-TSH (TSI/LATS). Detected by bioassay.
What auto-antibodies are associated with atrophic gastritis (pernicious anemia), and how are they detected?
Anti-parietal cell and anti-IF. IIF on cryostat sections of rat stomach/liver/kidney.
What auto-antibodies are associated with ulcerative colitis, and how are they detected?
pANCA. IIF on ethanol-fixed neutrophils.
What auto-antibodies are associated with celiac disease, and how are they detected?
Anti-gliadin, anti-endomysial, ,and anti-transglutaminase. ELISA; IIF on cryostat sections of rat stomach/liver/kidney.
What auto-antibodies are associated with autoimmune hepatitis, and how are they detected?
Anti-smooth muscle. IIF on cryostat sections of rat stomach/liver/kidney.
What auto-antibodies are associated with primary biliary cirrhosis, and how are they detected?
Anti-mitochondrial. IIF on cryostat sections of rat stomach/liver/kidney.
What auto-antibodies are associated with IDDM, and how are they detected?
Anti-islet cell, anti-glutamic acid decarboxylase (GAD), anti-insulin receptor. IIF on cryostat sections of pancreas; ELISA; bioassay.
What auto-antibodies are associated with autoimmune hemolytic anemia, and how are they detected?
Anti-Rh complex. Detection is not routinely done.
What auto-antibodies are associated with immune thrombocytopenic purpura, and how are they detected?
Anti-GPIIb, GPIIIa, GP1b, or GPV. Detection is not routinely done.
What auto-antibodies are associated with myasthenia gravis, and how are they detected?
Anti-AChR. Bioassay; ELISA.
What auto-antibodies are associated with SLE, and how are they detected?
ANA, anti-dsDNA, anti-Sm, anti-RNP, etc. IIF on C. luciliae or HEp-2 cells; ELISA.
Mixed connective tissue disease is a systemic condition with overlapping features of SLE, scleroderma, and/or dermatomyositis/polymyositis. What auto-antibodies are associated with MCTD, and how are they detected?
ANA, anti-RNP. IIF on C. luciliae or HEp-2 cells; ELISA.
What auto-antibodies are associated with drug-induced lupus, and how are they detected?
ANA, anti-histone. IIF on C. luciliae or HEp-2 cells; ELISA.
What auto-antibodies are associated with Sjogren syndrome, and how are they detected?
ANA, anti-SS-A (Ro), anti-SS-B (La), anti-nucleolar. IIF on C. luciliae or HEp-2 cells; ELISA.
Scleroderma (progressive systemic sclerosis) is associated with obliterative vasculopathy, dermal sclerosis, epidermal atrophy, tenosynovitis, esophageal sclerosis, interstitial lung disease, pulmonary hypertension, telangiectasia, calcinosis, and renal hypertension. What auto-antibodies are associated with scleroderma, and how are they detected?
ANA, anti-nucleolar, anti-Scl-70 (anti-topoisomeraseI). IIF on C. luciliae or HEp-2 cells; ELISA.
CREST syndrome (CREST variant of scleroderma) consists of calcinosis, Raynaud syndrome, esophageal dysmotility, sclerodactyly, and telangiectasias. What auto-antibodies are associated with CREST syndrome, and how are they detected?
Anti-centromere. IIF on C. luciliae or HEp-2 cells; ELISA.
Polymyositis/dermatomyositis is associated with proximal motor weakness and pain, heliotrope rash, Gottren syndrome papules, interstitial lung disease, possible internal malignancy. What auto-antibodies are associated with polymyositis/dermatomyositis and how are they detected?
Anti-Jo1 (tRNA synthetase). IIF on C. luciliae or HEp-2 cells; ELISA.
What auto-antibodies are associated with rheumatoid arthritis, and how are they detected?
RF (IgM anti-IgG), anti-keratin Ab (AKA), anti-RA33, anti RA-associated nuclear antigen (RANA). Detected by latex agglutination.
For the following thyroid disorders, what are %s for the presence of anti-thyroglobulin Ab, anti-microsomal Ab, and LATS/TSI (Long-Acting Thyroid-Stimulating/Thyroid-Stimulating Immunoglobulin, AKA TSH receptor) Ab: Hashimoto thyroiditis, other thyroiditis (de Quervain and lymphocytic), Graves disease, thyroid carcinoma?
Hashimoto thyroiditis: 60-100%, 80%, 0%. Other thyroiditis (de Quervain and lymphocytic): 30-50%, 50%, 0%. Graves disease: 30%, 60-80%, 100%. Thyroid carcinoma: 20-50%, 15%, 0%.
Autoimmune/lymphoplasmacytic/sclerosing pancreatitis is associated with elevation of serum IgG4 in ___% of cases.
Autoimmune/lymphoplasmacytic/sclerosing pancreatitis is associated with elevation of serum IgG4 in more than 70% of cases.