Immunology

Question 1

What immune disease is charactertized by:

 Presents approximately 2-6 months of age (after maternal antibody wanes)
 Extremely low or absent immunoglobulin levels (IgG <200 mg/dl)
 Recurrent upper respiratory infections, Giardia infestations

Answer 1

Bruton’s aggamaglobulinemia

The correct term now is Bruton’s Thymidine Kinase (BTK) Deficiency

CD19 positive B cells are absent in peripheral blood. Most common defect is in a B cell progenitor kinase, located on the long arm
of chromosome X (Xq22)
Treated with intravenous Immunoglobulin
An autosomal recessive form of this syndrome exists and is related to defects in the genes encoding the u heavy chain gene, CD79A and CD179B

Question 2

How do you differentiate Bruton’s agammaglobulinemia from transient hypoalbuminemia of infancy?

Answer 2

Trans Hypoalb will present approximately 5-6 months
IgG and IgA low, IgM may be normal to low
Recurrent upper respiratory infections
CD19 positive B cells ARE present
Hypogammaglobulinemia may last up to 2 years.
Cause is undefined

Question 3

What immune disease may be a B or T cell defect and can cause a Th1 imbalance with elevated IL12 and gamma interferon and it is autosomal recessive and from ICOS defect?

*These patients get recurrent upper and lower respiratory infections, intestinal bacterial overgrowth and Giardia intestinalis infection

Answer 3

CVID

B cells can’t differentiate into plasma cells

Germinal centers are HYPERplastic

Question 4

What immune disease presents in the first year of life, IgM levels are normal to elevated (100-1000 mg/dl), IgG, IgA and IgE levels are low, CD4 cell increase may occur and it is due to a defect is in the gene (Xq26 ) coding for the T cell protein, CD154 (CD40 Ligand) molecule?

Answer 4

CD40 Ligand Deficiency (used to be called Hyper IgM Deficiency)

CD154 binds to CD40 initiating class switching
in B cells. This defect prevents T cells from inducing B
cells to undergo a class switch. Thus the B cells
produce IgM, without switching to another isotype.
Autosomal recessive form does exist, involving the TNFRSF5 gene

Question 5

What is the mutation in DiGeorge syndrome?

Answer 5

Tbx1 mutation
Chromosome 22q11.2 missing in DiGeorge,

Question 6

What immune disease is characterized by IL-2 receptor gamma chain mutation, (Xq13); also affects receptors for IL-4, 7, 9, 15 and 21. Phenotype is T- B+ NK+or-?

Answer 6

SCID

Question 7

What immune disease is characterized by not having ANY T, B or NK cells (ie what the boy in the bubble had)?

Answer 7

Adenosine deaminase deficency

Question 8

What genes are involved in 1) MHC Class I deficiency and 2) MCH Class II deficiency?

Answer 8

Autosomal recessive disorder
– Class 1 deficiency- TAP1, TAP2 genes
– Class II deficiency- RFXAP, RFXANK genes

Question 9

What immune disease is characterized by:

Defect in CD18 gene (INTGB2 gene, 21q22.23), preventing proper LFA-1 adhesion molecule formation. This molecule is important in allowing neutrophils to migrate out of blood vessels into the tissues. It is autosomal recessive disease and causes recurrent soft tissue infections; impaired
wound healing?

Answer 9

Leukocyte Adhesion Deficiency, Type I

Question 10

This cell is a neutrophil engulfed Ab coated cell
nucleus. What disease can this be seen in (not real life but on boards)?

Answer 10

Lupus

Question 11

What ANA pattern is seen here and what antigens are present?

Answer 11

HOMOGENOUS

Antigens: DNA, histone, dsDNA, ssDNA

Associations: SLE, drug-induced lupus, RA

Question 12

What ANA pattern is this and what antigen is it associated with?

Answer 12

Anti dsDNA quantitation with Crithidia luciliae

The kinetoplast staining is positive dsDNA and will appear as two (sometimes three) dots. The only staining that is important is the KINETOPLAST

The other two dots that are staining regardless are the basal body and the nucleus but the nucleus is usually poorly visualized even if sera is ANA positive.

Question 13

What serum markers help differentiate lupus from mixed connective tissue disease?

Answer 13

MCTD will be positive with anti-RNP but NOT anti-smith

Lupus will be positive for both

Question 14

What ANA pattern is this and what antigen is it associated with?

Answer 14

SPECKLED

Antigen: SSA (Ro), SSB (La), Smith, U1-RNP, PCNA, Scl-70 (fine speckling)

Associations: SLE, MCTD, Sjogren, Scleroderma

Question 15

What immunologic findings do scleroderma patients display in regards to levels of CD4, CD8 and B cells?

Answer 15

Normal CD8 suppressor activity
Increased CD4 TH activity
Increased lymphokines
Increased B cell activation

Question 16

What ANA pattern is seen here and what antigen is this associated with?

Answer 16

NUCLEOLAR pattern

Antigens: RNA polymerase I, U3-RNP (fibrillarin), PM-Scl

*NOTE* if you see the nucleolar pattern with prominent green background staining, that is most likely specific to fibrillarin (U3-RNP)

Associations: Scleroderma, Polymyositis/Scleroderma overlap

Question 17

What ANA pattern is seen here and what antigen is it associated with?

Answer 17

Centromere

Antigens: CENP-A, B and C

Associations: scleroderma (with CREST syndrome), Raynoud

*NOTE* the mitotic cells show a speckled pattern whereas in the normal speckled pattern, you won’t see these mitotic figures

Question 18

What vasculitis is immune complex mediated?

Answer 18

Polyarteritis nodosa (secondary to SLE, HepB)

Question 19

What autoimmune vasculitis is antibody mediated?

Answer 19

Kawasacki disease (necrotizing vasculitis, primarily pediatric disease)

Question 20

Name three diseases associated with pANCA.

Answer 20

Churg Strauss

Microscopic polyangiitis

IBD (60-70% with UC, 40% with Crohn’s)

*Anti-Saccharomyces ceriviseae Ab (ASCA) is asssociated with Crohn’s

Question 21

Regarding c-ANCA and p-ANCA, what are these antibodies against?

Answer 21

cANCA is usually antibody to proteinase 3

pANCA is usually antibody to myeloperoxidase

*HINT* Remember that P ANCA does NOT go with P protein

Question 22

What is atypical (X) ANCA and what is it associated with?

Answer 22

UC and primary sclerosing cholangitis

Possible antigen targets: lactogerrin, cathepsin G, histone H1, BPI (bacterial permeability increasing protein)

Question 23

BQ! Explain the technical process for ANCA evaluation (actually pretty interesting process and according to OSLER guy, this shows up commonly on boards).

Answer 23

FIRST: Screen on ETOH fixed neutrophils
–Cytoplasmic speckling indicates cANCA
–Perinuclear or nuclear staining indicates either pANCA, ANA or
aANCA
SECOND: Run specimen on formalin fixed neutrophils

*why? Because during ethanol fixation, the granules in neutrophils coalesce around the nucleus where in formalin fixed neutrophils they stay out in the cytoplasm so on a FF slide there is NO difference in a C or P ANCA that is why screening is done on ethanol slides because you can tell the difference

–Cytoplasmic staining on FF fixed neutrophils suggest pANCA
– MPO remains in the cytoplasm during formalin fixation
–Negative result suggests ANA or xANCA
– Anti DNA may remain positive on FF neutrophils
THIRD: Run on Hep-2 to rule out ANA

Question 24

Shown are ethanol fixed neutrophils. What is this diagnostic of?

Answer 24

c-ANCA

*in ethanol fixed neutrophils, c-ANCA is cytoplasmic whereas perinuclear staining could be either p-ANCA, ANA, or atypical ANCA because the granules coalesce around the nucleus so if you get cytoplasmic staining on ethanol fixed, you have c-ANCA but if you have perinuclear staining, you have to then test formalin fixed neutrophils where BOTH c-ANCA and p-ANCA will stain the cytoplasm but will be negative if ANA or atypical ANCA is the culprit. So then follow it with Hep2 cells to check for ANA and if that is neg, you have atypical ANCA by exclusion.

Therefore cytoplasmic staining in ethanol fixed is c-ANCA. Perinuclear staining on ethanol fixed followed by cytoplasmic staining in formalin is p-ANCA. Perinuclear staining on ethanol followed by negative formalin followed by positive ANA Hep2 is ANA and if Hep2 is negative its atypical ANCA

Question 25

This is a mouse kidney. What antibody is this?

Answer 25

**Anti-mitochondrial antibody** 85% of PBC Reactive with the cytoplasm of parietal cells of the staomch and renal tubular cells in the mouse stomach/kidney substrate \*note AMA also seen in 10-15% of autoimmune hepatitis

Question 26

What antibodies are seen in autoimmune hepatitis (there are two types)?

Answer 26

Type 1- Anti-Smooth muscle Ab, ANA Type 2- Anti-Liver Kidney Microsomes (Cytochrome P450 D26)

Question 27

What immunodeficiency is more common in patients with Celiac disease?

Answer 27

IgA deficiency occurs more frequently in celiac disease than in the general population. – 1/700 in normal population – App 4% in celiac disease patients

Question 28

This is monkey esophagus. What is the antibody?

Answer 28

Anti-endomysial antibody (Celiac)

Question 29

What is the single best test for celiac disease?

Answer 29

IgA anti TTG is the best single test for Celiac Disease ## Footnote IgA Anti TTG and Anti Deamidated Gliadin appear to be the most useful combination of serological assays – If the above tests are negative, and the patient is IgA deficient, or if clinical suspicion of Celiac is still high, then an IgG anti TTG and IgG anti d-Gliadin is in order HLA Typing- DQ2 and DQ8

Question 30

What chromosomes are the following found: 1) kappa light chain genes 2) lambda light chain genes 3) heavy chain genes 4) HLA proteins

Answer 30

1) Chr 2 2) Chr 22 3) Chr 14 4) Chr 6p

Question 31

What is the gold standard for detecting HLA antigens, HLA antibodies and performing HLA crossmatching?

Answer 31

Complement dependent cytotoxicity assay (CDC)

Question 32

What do the following luminex values correspond to in HLA testing: 1) \>5,000 MFI 2) \>10,000 MFI

Answer 32

1) correlates with a positive T cell and B cell flow crossmatch 2) correlates with a positive CDC, indicating hyperacute rejection is likely if organ is transplanted

Question 33

What immune disease typically appears in the 2nd or 3rd decade of life and is characterized by recurrent upper and lower respiratory tract infections, intestinal bacterial overgrowth, Giardia infection, bronchiectasis, low IgG, low IgM, low IgA and variable T cell deficiency?

Answer 33

CVID These patients will have lymphoid hyperplasia with decreased/absent plasma cells on biopsy

Question 34

What disease have increased IgE (3) and decreased IgE (2)?

Answer 34

Increased IgE: Wiskott-Aldrich, Job syndrome (hyper-IgE) and Nezelof syndrome Decreased IgE: Bruton agammaglobulinemia and Ataxia-telangectasia

Question 35

What immune disease has been linked to in utero exposure to Accutane?

Answer 35

DiGeorge Syndrome Microdeletions involving chr 22q11.2

Question 36

What immune disease is characterized by deficient IgA (hint I am not getting at IgA def here), VERY HIGH serum AFP and CEA, and is due to mutations in the ATM gene on 11q22.3?

Answer 36

Ataxia telangectasia \*opposite of DiGeorge which is 22q11 and this disease is 11q22

Question 37

What disease is from mutations in autoimmune regulator gene (AIRE) on chromosome 21q22.3?

Answer 37

Chronic mucocutaneous candidasis

Question 38

What disease causes a fulminant and often fatal immune response to EBV, has inverted CD4:CD8 ratio, hypogammaglobulinemia and the underlying abnormality is from mutation of SH2D1A gene Xq25 which codes for an SH2 domain on a signal transducing protein called SLAM associated protein (SAP)?

Answer 38

Duncan disease (X linked lymphoproliferative disorder)

Question 39

What anomaly is characterized by fat vacuoles in leukocytes?

Answer 39

Jordan anomaly

Question 40

What are the lab findings in C1 esterase inhibitor deficiency (hereditary angioedema)?

Answer 40

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 Treatment: used to be FFP but in 2008 **recombinant C1 esterase inhibitor concentrate** became available which is now first line therapy

Question 41

What is the MHC gene association for hereditary hemochromatosis?

Answer 41

HLA A3

Question 42

What is the MHC gene association for 21 hydroxylase deficiency?

Answer 42

HLA C4

Question 43

What is the MHC gene association for ankylosing spondylitis and Reiter's syndrome?

Answer 43

HLA B27

Question 44

What is the MHC gene association for Behcet's disease?

Answer 44

HLA B51

Question 45

What is the MHC gene association for celiac sprue?

Answer 45

HLA DQ2, DQ8

Question 46

What is the MHC gene association for DM type 1?

Answer 46

HLA DR3 or DR4

Question 47

What is the MHC gene association for multiple sclerosis?

Answer 47

HLA DRB1, DQB1

Question 48

What is the MHC gene association for narcolepsy?

Answer 48

HLA DQ6

Question 49

What is the MHC gene association for RA and pemphigus vulgaris?

Answer 49

HLA DR4

Question 50

What mneumonic helps to remember what drugs cause drug induced lupus?

Answer 50

"SHIPP, May Day" Sulfasalazine Hydralazine Isoniazid Procainamide Penicillin Methyldopa Dilantin

Question 51

A patient is very likely to have what disorder if they have positive ANA, positive SS-A but negative SS-B?

Answer 51

Lupus nephritis

Question 52

Other than sarcoidosis, what disease have elevated ACE?

Answer 52

Gaucher Leprosy PBC

Question 53

PBC and autoimmune hepatitis both have hypergammaglobulinemia due to a polyclonal increase of which antibody (different for each)?

Answer 53

PBC polyclonal IgM AIH polyclonal IgG

Question 54

The lesion shown is characteristic of what disorder? HINT: it involves medium sized vessels and typically spares the lungs and involves the kidney, nerves, mesenteric vessels and skin?

Answer 54

Polyarteritis nodosa Pic is showing the characteristic lesion of segmental fibrinoid necrosis of the vessel wall The segmental nature of involvement with active and healing lesions next to normal segments of blood vessel is highly characteristic

Question 55

Name this disease. Autosomal recessive disorder caused by anomalies in the MEFV gene on chromosome 16 which encodes pyrin/marenostrin protein and is characterized by paroxysms of fever and pain related to inflammation of the serosal membranes (peritoneum, pleura, synovium, or tunica vaginalis) and amyloidosis with renal failure is a complication (AA type)?

Answer 55

Familial Mediterranean Fever this is the prototype "autoinflammatory fever syndrome"

Question 56

*Q from Q book but I have trouble remembering this concept:* Which of the following is **NOT** an example of type IV hypersensitivity? a) contact dermatitis b) multiple sclerosis c) myasthenia gravis d) rheumatoid arthritis e) type I DM

Answer 56

**Myasthenia gravis** (it is a type II hypersensitivity) ## Footnote These type IVs don't make sense to me because by definition they are not supposed to be antibody mediated yet almost all these diseases have characteristic autoantibodies-- so just memorize **_Type IV hypersensitivity_**: contact dermatitis (ie poison ivy), multiple sclerosis, rheumatoid arthritis, type I diabetes, Crohn's disease and Hashimoto's

Question 57

What are the serum antibody patterns seen in Wiskott-Aldrich?

Answer 57

Serum IgG normal IgM low IgA and IgE high

Question 58

What immune disease is characterized by leukocytes being deficient in C3b receptors and their red cells often bear the McLeod phenotype (absence of Kell antigen, Kx)?

Answer 58

**Chronic granulomatous disease** McLeod phenotype shows red cells with acanthocytosis Other disease associated with McLeod phenotype: a late onset type of muscular dystrophy ("neuroacanthocytosis") and retinitis pigmentosa

Question 59

What is the CD4 count of an HIV patient with CMV retinitis?

Answer 59

\<50

Question 60

The hemodialysis associated systemic form of amyloidosis is associated with which amyloid protein?

Answer 60

**Aß₂M** ß₂ microglobulin is a component of the MHC class I molecule that is deposited in patients undergoing long term dialysis Other types: **AL** = primary amyloidosis resulting from conditions like myeloma and other monoclonal B cell proliferations **AA or serum amyloid associated protein** = produced in the liver and is associated with secondary amyloidosis from chronic inflammatory conditions such as RA, AS, IBD, heroin abusers as well as neoplasms such as RCC and Hodgkin's **Transthyretin (TTR)** = protein that transports retinol and thyroxine and its mutant form is deposited in familial amyloid polyneuropathies and senile systemic amyloidosis **Aß (ß amyloid protein)** = forms the core of cerebral plaques in Alzheimer's

Question 61

What are the following amyloid proteins associated with? 1) Aß2M 2) AL 3) AA 4) Transthyretin 5) Aß

Answer 61

**Aß2M** = ß2 microglobulin is a component of the MHC class I molecule that is deposited in patients undergoing long term dialysis ## Footnote **AL** = primary amyloidosis resulting from conditions like myeloma and other monoclonal B cell proliferations **AA or serum amyloid associated protein** = produced in the liver and is associated with secondary amyloidosis from chronic inflammatory conditions such as RA, AS, IBD, heroin abusers as well as neoplasms such as RCC and Hodgkin's **Transthyretin (TTR)** = protein that transports retinol and thyroxine and its mutant form is deposited in familial amyloid polyneuropathies and senile systemic amyloidosis **Aß (ß amyloid protein)** = forms the core of cerebral plaques in Alzheimer's

Question 62

What cells express MHC Class I antigens? MHC Class II?

Answer 62

_Class I_: Surface of most nucleated cells _Class II_: B cells, monocytes, macrophages, dendritic cells and activated T lymphocytes

Question 63

There are 3 main targets of acute GVHD, what are the histologic findings? * Skin * Intestinal tract * Hepatobiliary tract

Answer 63

Acute GVHD occurs within the first 100 days with most cases presenting within the first 30 days * Skin--erythematous pruritic rash, erythema multiforme like apoptosis that is most pronounced at base of rete ridges * Intestinal tract--diarrhea, histologically ectatic crypts with attenuated enterocytes, crypt abscesses and striking apoptosis within the crypt epithelium * Hepatobiliary tract--liver involvement presents with jaundice char by mononuclear portal inflammatory infiltrates with endothelialitis, ductitis and ductopenia Chronic GVHD happens after the first 100 days and in addition to above shows mucosa and respiratory tract involvement. They get extensive cutaneous sclerosis similar to progressive systemic sclerosis pts. They may experience esophageal strictures, bronchiolitis obliterans, scarring ocular lesions and chronic liver damage. **This is different from TA-GVHD where the primary target is bone marrow and 90% of these pts die and this can be prevented by irradiated units**

Question 64

What is the most common inherited immunodeficiency disease?

Answer 64

Selective IgA deficiency (1 in 700)

Question 65

What are the IgG4 related sclerosing diseases?

Answer 65

* Sclerosing mediastinitis * Idiopathic retroperitoneal fibrosis * Riedel thyroiditis * Sclerosing cholangitis * Orbital pseudotumor * Sclerosing pancreatitis

Question 66

What antibody is this staining?

Answer 66

Anti-smooth muscle Autoimmune hepatitis