L14: Inherited Immunodeficiencies Flashcards
1
Q
How are immunodeficiencies caused?
A
defects in germ-line DNA
2
Q
What is asplenia?
A
Lack of spleen or its normal function. elevated susceptibiility to encapsulated bacterial pathogens (eg: strep pneum, haemophilus influenzae). Tend to develop sepsis with these pathogens
3
Q
What are the two major blood filters in the body?
A
spleen and liver. Can be acquired (from spleen injury) or inherited
4
Q
What will defects in recruitment of phagocytes to the extravascular sites of infection cause?
A
severe immunodeficiency. Phagocytes reach these sites by emigrating from blood vessels, and the process is mediated by cell adhesion molecules. Results in infections that are antibiotic resistant and persist in spite of apparently effective cellular and humoral immune responses
5
Q
What is leukocyte adhesion deficiency?
A
a type of phagocyte deficiency that prevents phagocyte recruitment to extravascular areas of infection
6
Q
What is chronic granulomatous disease?
A
phagocytes cannot produce reactive oxygen compounds (notably superoxide radical) to kill bacteria. It is usually an autosomal recessive X-linked trait, caused by mutation in gp91 protein (p91-PHOX).
Characterized by chronic bacterial infections that can lead to granulomas
7
Q
What is myeloperoxidase deficiency?
A
macrophages are unable to efficiently kill phagocytosed microbes because of impaired production of hypochlorous acid and toxic oxygen species. Normal respiratory burst, but inability to form bleach to kill. Not as severe as if entire respiratory burst was defective.
8
Q
What is Chediak-Higashi syndrome?
A
complex syndrome characterized by partial albinism, abnormal platelet function , and severe immunodeficiency. Results from defective gene encoding of protein necessary for intracellular vesicle formation, causing failure of lysosome:phagosome fusion. Phagocytes impaired ability to kill bacteria
9
Q
What are neutorpenias?
A
diseases characterized by low numbers of granulocytes, usually defined as a neutrophil count of less than 500 cells/uL (normal is 2000 cells/uL)
10
Q
What are the three most common types of neutropenias?
A
- severe congenital neutropenia (Kostmann syndrome)
- cyclic neutropenia
- benign chronic neutropenia
11
Q
What is Kostmann syndrome?
A
(severe congenital neutropenia) an autosomal recessive disorder associated with a gene abnormality of granulocyte colony stimulating factor (G-CSF) or its receptor (G-CSFR. These stimulate granulocyte growth
12
Q
What is cyclic neutropenia?
A
an autosomal dominant disorder in which the neutropenia occurs every 2-4 weeks and lasts about a week. It is associated with a gene defect termed ELA-2
13
Q
What is benign chronic neutropenia?
A
low but not life-threatening neutropenia that is often asymptomatic
14
Q
What are some primary immunodeficiencies that have associated neutropenia?
A
X-linked hyper-IgM syndrome
X-linked aggamaglobulinemia (XLA)
WHIM syndrome
Griselli syndrome
15
Q
What are the three categories of NK cell defects?
A
- absolute NK cell deficiency (ANKD)
- Classical NK cell deficiency (CNKD)
- functional NK cell deficiency (FNKD)
16
Q
What are ANKDs?
A
NK cell defects that involve either the complete absence of NK and NKT cells or a total lack of function
17
Q
What are CNKDs?
A
lack of NK cells and function. Presence of NKT cells
18
Q
What is FNKD?
A
normal or near normal NK cell numbers, but absent or severely decreased NK cell function. Usually have NKT cells
19
Q
How are NK cell defects diagnosed?
A
flow cytometry
20
Q
What are the clinical presentations of NK cell defects?
A
highly variable, but typically increased incidence and severity of viral and other infections, especially varicella zoster, herpes, cytomegalovirus, epstein-Barr, mycobacterium, MAI, trichophytons
21
Q
What are trichophytons?
A
fungus that are one of the leading causes of hair, skin and nail infections
22
Q
What genetic defects can result in NK cell defects?
A
defective formation of cytoplasmic granules
defective porforin
defects in bone marrow development
23
Q
What vulnerability would you expect from defects in Toll-like receptors?
A
dramatically reduced ability to recognize gram-negative bacteria.
24
Q
What is NEMO?
A
X-linked hypohydrotic ectodermal dysplasia and immunodeficiency. Is an genetic deficieny in which PRRs are intact, but transcription of the genes that should be expressed following recognition is deficient.
Also commonly see developmental defects like deep-set eyes, sparce hair, conical teeth and skin conditions.
Patients suffer from recurrent bacterial and viral infections.
25
What is NFkB?
an important transcription factor for physical development as well as innate immunity.
26
Do TLRs have any effect on NFkB?
yes, toll-like receptors activate NFkB, which controls cytokine/chemokine expression
27
How is NEMO treated?
biweekly injections of gamma globulin from a healthy donor or bone marrow transplants
28
Complement deficiencies have similar clinical presentations as what deficiencies?
antibody deficiencies. They are prone to many of the same infections
29
What happens with defects in C3?
wide range of infections by encapsidated bacteria. C3b plays a huge role in opsonization to promote phagocytosis
30
What do defects in membrane attack components of the complement do? Which complement factors are those?
C5-C9. Defects in these have more limited effects and result in susceptibility only to Neisseria species
31
What happens if there are defects in the early stages of the classical complement cascade?
immune complexes accumulate, causing tissue damage (phagocytes cannot recognize them as well)
32
What can deficiencies in control proteins that regulate complement activation cause?
either immunodeficiency or auto-immune-like diseases
33
What will a defect in properdin P do? What does properdin P do?
Properdin P enhances activity of the alternative complement pathway. Defects in this will lead to heightened sensitivity to Neisseria species
34
What happens in patients who lack DAF and CD59?
These protect host cell surfaces against the complement cascade. Defects in these result in destruction of red blood cells, causing paroxysmal nocturnal hemoglobulinuria
35
What happens in patients with C1-inhibitor defects?
HANE. (hereditary angioneurotic edema) they fail to control the innappropriate activation of the classical complement cascade, resulting in uncontrolled cleavage of C2, allowing generation of C2b, which causes fluid accumulation in tissues and epiglottal swelling that can kill.
Overproduction of anaphylatoxins
36
What defect could cause paroxysmal nocturnal hemoglobulinuria?
defects in DAF and CD59, which protect self-cells from the complement cascade
37
What is the primary clinical result of defects in antibody production?
inability to control extracellular bacteria that produce polysaccharide capsules (resistant to phagocytosis). They are also more suceptible to viruses (enteroviruses) that are sensitive to neutralizing Abs
38
What is XLA? What defect causes it?
X-linked agammaglobulinemia. absence of immunoglobulin in the serum.
Defect in Bruton's tyrosine kinase (Btk), which is needed for transduction signals from cell-surface receptors during B cell development. This halts B cell maturation in the pre-B cell stage. Results in lack of functional B cells and susceptibility to extracellular bacteria and many viruses.
X-linked
39
What wil selective IgA deficiency cause?
most people in developed countries are healthy. Parasitic infections can be a problem. IgM can transport across mucosal epithelium to act for IgA.
40
What results form selective IgG1 deficiency?
very rare, but leaves person susceptible to many bacterial and viral pathogens
41
What results form selective IgG2 deficiency? Who is it most common in?
most common in kids, susceptible to encapsulated bacteria
42
Who is IgG3 deficiency most common in?
most common in adults
43
What results form selective IgG4 deficiency?
seemingly nothing
44
What is the most abundant IgG molecule? Least?
IgG1 (70%)
| IgG4 (1-3%)
45
What is X-linked hyper-IgM syndrome?
inherited disease characterized by high serum IgM, but very low concentrations of other Abs. Commonly from defects in the CD40 ligand on T cells, preventing them from interacting with CD40 on B cells, leaving B cells inactive.
This causes profound immunodeficiency and failure to generate germinal centers.
Can also be caused by defect in AID (activation-induced cytidine deaminase), which is required for isotype switching and somatic hypermutatoin. This does not prevent T cell help to B cells
46
What is CVID?
common variable immunodeficiency. a group of 150 primary immunodeficiencies that have common features that typically include reduced levels of Ab, but different etiologies. Genetic cause usually doesn't occur until 20s or 30s. Recurring infections with bacterial and viral pathogens in ears, eyes, nose, sinuses, bronchi, lungs, skin, GI, joints, bones, CNS, parotid glands. Hypogammaglobulinemia is tpical but not as dramatic as in XLA.
47
What do TAP peptide transporter deficiencies cause?
```
result in very low levels of MHC class I molecules and defective responses to intracellular pathogens due to CD8 T cell deficiency. Results in significantly decreased T cell selection during thymic development.
Can also be called bare lymphocyte syndrome, but this usually refers to a MHC class II deficiency so be careful.
```
48
What is a CD8 alpha chain defect?
lack of CD8 expression that has the same phenotype as a TAP transporter deficiency - very low CD8 T cells.
49
What will a nonsense mutation in perforin cause?
results in dramatically or total reduction in CTL activity, but normal numbers of CD8 T cells. CTLs are unable to induce programmed cell death of targets
50
What is SCID?
severe combined immune deficiency. When a person has defects in both CD4 and CD8 T cells. They are also unable to mount antibody response because B cells cannot be activated
51
What does adenosine deaminase deficiency (ADA) cause?
results in SCID phenotype and accumulation of nucleotide catabolites that are toxic to developing T and B cells
52
What does purine nucleotide phosphorylase deficiency (PNP) cause?
results in SCID phenotype and accumulation of nucleotide catabolites that are toxic to developing T and B cells
53
What is bare lymphocyte
lack of expression of MHC class II molecules which results in an inability of CD4 T cells to be positively selected in the thymus. Those that do make it cannot be activated due to lack of MHC class II on APCs.
54
What is DiGeorge syndrome? (not the complete form)
results from small deletion in chromosome 22 that causes congenital heart disease, palatal abnormalities, learning disabilities, hypocalcemia, and mild facial differences.
55
What is complete DiGeorge syndrome?
DiGeorge's but also have absent or under developed thymus, therefore little to no T cells. Susceptible to fungal, bacterial and viral infections common in SCID. Treat with thymic transplant.
56
What does common gamma chain deficiency cause?
X-linked gene. Common gamma chain is the signaling component for many cytokine receptors (IL-2, IL-4, IL-7, IL-9, IL-15). It interacts with Jak3 to initiate signaling once cytokine receptor has be engaged. Defects in this cause failure to initiate signaling of any of these cytokine receptors and SCID develops.
57
What will a Jack3 deficiency cause?
Jak3 interacts with common gamma chain to initiate signaling after cytokine binding of IL-2,4,7,9,15. Causes SCID if defective.
58
What is Omenn Syndrome?
missense mutations that result in defective RAG, which results in absence of B cells and a small number of auto-reactive T cells. Patients are vulnerable to many infections, have SCID - same phenotype as common gamma chain deficiency. Causes erhtyrodema, desquamation, alopecia, chronic diarrhea, failure to thrive, lymphadenopathy, and hepatosplenomegaly
59
What does ZAP deficiency cause?
Bonnie's Aliens. ZAP-70 is a tyrosine kinase that associates with ITAMS during signalling via the TCR complex. (required for T cell signaling via TCR). Deficiency causes absence of CD8 T cells, normal number of CD4 but they are dysfunctional, causing SCID. Treat with bone marrow transplant.
60
What is APECED?
autoimmune polyendocrinopathy condidiasis ectodermal dystrophy. Defect in AIRE, causes a lot of autoimmune syndromes. Characteristically causes glandular problems, latent hypothyroidism, baldness, tooth enamel hypoplasia, candidiasis, anemia and GI problems
61
What is AIRE?
transcription factor that regulates expression of several hundred host-tissue specific genes in the thymic medulla. Necessary for negative thymic selection against self-binding cells.
62
What is IPEX?
Immune Dysregulation, Plyendocrinopathy, Enteropathy, X-linked syndrome.
Deficiency in FoxP3 expression in regulatory CD4 T cells results in early onset of autoimmunity due to lack of Treg cell function. Watery diarrhea, dermatitis, endocriopathy, Coombs-positive anemia, autoimmune thrombocytopenia, neutropenia, and tubular nephropathy. Treat with immune suppression and bone marrow transplants.
63
What is ALPS?
autimmune lymphoproliferative syndrome. Characterized by lymphadenopathy and splenomegaly. Results from immune cells failing to undergo apoptosis following immune responses, causing overpopulation of secondary lymph tissue. Caused by mutations that prevent Fas, Fas ligand, or caspase 10. Causes anemia, neutorpenia, thrombocytopenia, lymphadenopathy, spenomegaly.
Usually large number of CD4 and CD8 T cells. Treat with immunosuppression and IVIg
64
What is Good's syndrome?
immunodeficiency with thymoma. adult-onset immunodeficiency that exhibits hypogammaglobulinemia, few or absent B cells, low CD4:CD8 ratio, CD4 lymphopenia, and impaired T cell mitogenic responses, reduced serum IgG, IgA, and IgM. Can have raised IgA and low everything else. Benign thymic tumors common. Causes opportunistic infections. Cuase unknown, but treat by removing thymic tumors and doing marrow transplants
65
What is WHIM syndrome?
Warts, hypogammaglobulinemia, infections and Myelokathexis. autosomal dominant immunodeficiency that causes increased infection susceptibility, especially to HPV, causing warts on hands and feet in childhood. Nuetrophils remain in bone marrow and lymphocytes and Ab levels low. Result of defect in CXCR4 (alpha-chemokine receptor specific for SDF-1 (CXCL12) that causes it to be permanently activated.
66
What is Myelokathexis?
retention (kathexis) of neutrophils in bone marrow.
67
What is CHH?
cartilage hair hypoplasia. results in short stature, shorter arms and legs, sparse hair, anemia, and immune problems. Impairment of T cells, neutorpenia and lymphopenia. Results in low resistance to varicella-zoster. Autosomal recessive.
68
What is Fanconi's anemia (FA)?
genetic defect in proteins responsible for DNA repair. Most develop cancer. Bone marrow failure by age 40. Congenital defects, short stature, abnormal, skin, arms, head, eyes, kidneys and ears, and developmental disabilities. Also endocrine problems. Usually kills by 30. Treat with androgens, blood cell growth factors, and marrow transplants
69
What is Griscelli syndrome?
albinism, immunodeficincy, early childhood death. impaired NK cell activity, absent delayed-type hypersensitivity and poor cell proliferation. Defect in vesical transport system that is common to melanocytes as well as NK and T cells. Proteins: Rab27A, Slac2-a, myosin Va.
70
Describe the mechanism of melanosome transport?
melanosomes transported on microtubules and bound to Rab27A, which recruits Slac2-a and myosin Va. This complex then transfers the melanosomes from the microtubules to actin filaments. Loss of any of these proteins causes hypopigmentation and also disrupts transport vesicle transport in NK and T cell and cytokine signal and granule content delivery
71
What is serum sickness?
a life-threatening complication that can sometimes occur when replacement therapy uses non-human serum infusions. (usually horse)
72
What causes the majority of immunodefiiencies?
defects in hematopoietic stem cells. Can be treated with bone marrow transplants.
73
What are the disadvantages of fetal cord blood?
small sample size, but you avoid invasive procedures
74
What is GVHD?
graft-vs-host disease. Mature T cells from donor transplant will attack recipient tissues. Can reduce risk of this by filtering out T cells prior to transplant, but htis increases risk of rejection. (SCID patients have no immune system to reject something with anyway so usually doesnt matter)..
Need to try to match HLA between donor and recipient to prevent alloreaction and promote T cell positive selection in thymus.
75
What is gene therapy?
functional copies of the defective gene are introduced into stem cells derived from the patients bone marrow and then these stem cells are re-infused into the patient.
76
What would a deficiency in glucose-6-phosphate dehydrogenase cause?
G6DP deficiency messes up respiratory burst and impairs killing of phagocytosed bacteria. Causes chronic infections and anemia.
77
What will a deficiency of myeloperoxidase cause?
impaired production of toxic oxygen species (bleach) and inability to kill phagocytosed bacteria, causing chronic infections. Normal respiratory burst, but reduced ability to kill
78
What disease will you get if you have a defect in vesicle fusion mechanics?
Chediak-Higashi. Impairs phagocytosis and ability to fuse endosomes with lysosomes. Cuases granulomas and persistant infections.
79
What will happen if you have defective NADPH oxidase?
phagocytes will be unable to produce O2 and it will impair killing of phagocytosed bacteria, causing chronic infections and granulomas.
80
What will happen if you have defective CD18?
CD18 is an adhesion molecule. Patient will have defective phagocyte migration to infected tissues, causing widespread infections by capsulated bacteria
81
What is an NKT cell?
atypical cell types that make up 0.1% of NK cells. recognize peptides bound to nonclassical MHC molecules.
82
How do NK cells kill mycobacterium avium?
ADCC (antibody-mediated)
83
Which Fc receptors bind to IgM?
there are no Fc receptors for IgM. IgM activates complement cascade and opsonins, which then allow phagocytosis.
84
What would deficiency in C1, C2, C4 cause?
classical pathway deficiency will cause immune-complex buildup (especially in kidney)
85
What will result from C3 deficiency?
susceptibility to capsulated bacteria. It will also knock out the MAC, so Neisseria dangerous too
86
What does Factor D do? Factor P?
Factor D cleaves factor B once it binds to C3b. Factor P stabilizes C3 convertase of alternative pathway.
87
What will a deficiency in Factor D or Factor P cause?
susceptibility to capsulated bacteria and Neisseria, but no immune-complex disease
88
What will a deficiency in Factor I cause?
depletion of C3 in tissues. Wont be able to respond to capsulated bacterial infections.
89
What will C1INH deficiency cause?
HANE
90
What will DAF or CD59 deficiencies do?
cause autoimmune conditions including paroxysmal nocturnal hemoglobinuria
91
What will MBL deficiency cause?
mannose-binding lectin binds to mannose on bacterial surfaces and becomes a substrate for MASP, activating lectin complement cascade. Deficiency will cause recurrent severe infections.
92
What will glycophosphatidylinositol deficiency cause?
glycophosphatidylinositol is required for surface expression of CD59 and DAF (complement control proteins that interfere with MAC formation). This will cause paroxymal nocturnal hemoglobinuria and red urine.
93
What will pre-B cell lambda-5 deficiency cause?
lambda-5 receptor is componenet of surrogate light chain that pairs with the Mu heavy chain during somatic recombination of light chain genes. Defects will result in inability of developing B cells to produce a pre-B cell receptor and they undergo apoptotic death. Causes profound B cell deficiency and susceptibility to both extracellular bacteria and many viral pathogens
94
If you have defective CD40 what will happen?
B cells will not be able to receive secondary activation signal.
Also prevents macrophage activation, making them vulnerable to intracellular infections.
95
What two things could cause X-linked hyper IgM syndrome?
```
defect in CD40 which will prevent helper T cell activation and B cell activation
or
AID deficiency (activation-induced cytidine deaminase)
```
96
A defect in which IgG will cause susceptibility to encapsulated bacteria?
IgG2, this is most common in kids.
97
Which IgG is vital to NK cell function?
IgG1
| MHC I is also very important
98
What is Wiskott-Aldrich syndrome?
defect in cytoskeletal reorganization that is needed for T cell to deliver cytokines and other signals to B cells and macrophages (cell cross-talk deficiency)
99
What will a CD3 deficiency cause?
lack of CD4 and CD8 T cells. Total lack of T cell function.
| Can be in the CD3 delta, epsilon or zeta chains.
