Immunodeficiency Flashcards

1
Q

Define Primary and secondary immunodeficiency

A
  • primary - congenital (the result of a failure of proper development of the humoral or cellular immune systems) The primary diseases are rare (1:2000 or less),
  • secondary - acquired (the consequences of other diseases and their treatments). the secondary diseases are much more common.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What are the four components of immunodeficiencies?

A
  • T cells
  • B cells
  • Phagocytes and Complement
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What do T cell deficiencies predispose you to?

What about the B Cells, Phagocyte, and complement deficiencies?

A

T cells predispose to infections with
• intracellular organisms including mycobacterium, fungi, and viruses.

Defects involving the three other primary components tend to result in
• extracellular bacterial infections.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

How do you evaluate antibody mediated immunity deficiencies?

A
  1. serum immunoelectrophoresis
  2. quantitation of immunoglobulins in serum and secretions
  3. detection of specific antibodies
    a) Schick test - for IgG diphtheria anti-toxin
    b) specific antibody responses - before and after immunization with killed vaccines
  4. quantitation of circulating B-cells by flow cytometry with mAbs to surface Ig
  5. induction of B-lymphocyte differentiation in vitro
  6. lymph node biopsy
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Evaluation of cell-mediated immunity

A
  1. DTH skin tests to common antigens - candida, streptokinase, streptodornase 6
  2. total lymphocyte count: 60-80% of peripheral blood lymphocytes are T-cells.
  3. enumerate T-cells and T cell subpopulations using mAbs to CD3, CD4 and CD8
  4. lymphocyte proliferation to lectins (PHA) and alloantigens – Mixed Lymphocyte Reaction
  5. in vitro analysis of T-lymphocyte function: production: IFNγ, IL-2; cellular cytotoxicity
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Evaluation of phagocyte function

A
  1. total granulocyte and monocyte count
  2. chemotaxis assay - Boyden chamber
  3. assay for phagocytosis using opsonized particles and for bacterial killing
  4. test for superoxide generation using nitroblue tetrazolium (NBT) reduction
  5. assay for individual enzymes and for cytokines (IL-1 and IL-12)
  6. response to activation by cytokines (IFNγ, GM-CSF)
  7. Antigen processing and presentation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Evaluation of the complement system

A
  1. total hemolytic complement assay - CH50 a functional assay
  2. immunoassay of individual complement components
  3. neutrophil chemotaxis assay using C in patient’s serum as a chemoattractant
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Antibody and B cell deficiencies

A

• Patients with stem cell and Bruton’s disease have few or no B cells or antibodies.
• biochemical abnormalities of the B cell lineage or defective regulation by T cells, e.g. as a result of the absence of T-helper activity
• antigen presentation or other cytokine abnormalities may be
• since different classes of Ig are regulated by different T helper cells, selective antibody class (IgA or IgG) deficiencies may result from abnormalities in T cell subpopulations
o Th1 cells help IgG1 and IgG3 responses
o Th2 cells help IgA and IgE responses

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is Bruton’s Disease?

A

• B cells fail to develop: congenital agammaglobulinaemia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What is X-linked agammaglobulinaemia? Are T cells normal?

A

• B cell precursors fail due to a defective gene encoding a tyrosine kinase (btk) involved in activation of the pre-B cell to immature B cell; T cells are normal

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What is Hyper-IgM syndrome?

A
  • B cells do not switch antibody isotype
  • increased IgM but little or no subclasses from IgG
  • defective gene coding for either CD40 on B cells or CD40L (CD 145) on T cells
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is Common Variable IgG/IgA Immunodeficiency (CVID)?

A
  • low IgG (often low IgA too) together with impaired specific antibody production in response to infections and vaccines.
  • the absence of T-helper activity or B cells that do not respond to signals from other cells.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Selective IgA deficiency is the most common primary immunodeficiency (1/700). Many patients do not present with significant disease, but they may have increased rate of upper respiratory infections.
•Patients have serum IgA levels less than 5 mg/dl with normal levels of other immunoglobulin classes, normal serum antibody responses, and normal cell mediated immunity.
•As many as 50% of patients with IgA deficiency have chronic otitis, sinusitis, pneumonia or diarrhea (IgA is the major Ig in mucosal secretions).
•Possible anaphylaxis following blood transfusion (patients have anti-IgA antibodies, and there is IgA in transfused blood!)
•Increased incidence of autoimmune disease

A

Selective IgA deficiency is the most common primary immunodeficiency (1/700). Many patients do not present with significant disease, but they may have increased rate of upper respiratory infections.
•Patients have serum IgA levels less than 5 mg/dl with normal levels of other immunoglobulin classes, normal serum antibody responses, and normal cell mediated immunity.
•As many as 50% of patients with IgA deficiency have chronic otitis, sinusitis, pneumonia or diarrhea (IgA is the major Ig in mucosal secretions).
•Possible anaphylaxis following blood transfusion (patients have anti-IgA antibodies, and there is IgA in transfused blood!)
•Increased incidence of autoimmune disease

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Deficiencies in IgG subclasses are often asymptomatic, but they may have increased respiratory infections.

Transient hypogammaglobulinemia of infancy is defined as an abnormally low amount of IgG, which leads to increased bacterial and virus infections. This resolves spontaneously by age 4.

A

Deficiencies in IgG subclasses are often asymptomatic, but they may have increased respiratory infections.

Transient hypogammaglobulinemia of infancy is defined as an abnormally low amount of IgG, which leads to increased bacterial and virus infections. This resolves spontaneously by age 4.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are the general traits of T cell deficiencies

A
  • very rare, these deficiencies result in compromised humoral immunity as well.
  • may relate to T cell subsets (e.g. CD8), other T cells may be normal.
  • recurrent viral, fungal, mycobacterial, and protozoan infections and present early in life.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What is DiGeorge syndrome?

A
  • due to an absent or very small thymus.

* severity depends on the amount of thymus present.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What is bare lymphocyte syndrome?

A
  • Defects in MHC class II expression lack CD4+ T cells
  • Defects in TAP1 or TAP2 genes lead to lack of MHC class I expression and CD8+ cells
  • SCID phenotype
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What is Wiskott-Aldrich syndrome (WAS)?

A
  • a mutation in the WAS protein

* a T cell signaling pathway protein in cytoskeletal mechanisms for T cell activation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What is Ataxia-telangiectasia?

A
  • mutations in the ATM protein (AT mutated)
  • involved in DNA repair
  • a normal checkpoint protein if DNA is damaged.
  • This results in impaired lymphocyte development and function.
20
Q

What is Severe Combined ImmunoDeficiency (SCID)

A

• affects B cell and T cell development or function

21
Q

What are some Stem cell defects in SCID?

A

• 50% have a defect in the cytokine γ chain used by many cytokine receptors
o IL-2, IL-4, IL-7, IL-9, IL-15, IL-21
o Thus T and NK cells dependent upon these cytokines do not develop
• 10% have adenosine deaminase (ADA) deficiency or thymocytes purine nucleoside phosphorylase deficiency.
o leads to toxicity in lymphocytes due to a buildup of purine metabolites which inhibit DNA synthesis.
o One therapeutic approach for this defect is to replace ADA through gene therapy of patient stem cells.
• 30% of SCID patients have defects in DNA recombination, thus they cannot produce functional Immunoglobulin or T cell receptors.
o In this case, no functional B or T cells develop in these patients.

22
Q

What are the two categories of phagocytic deficiencies?

A
  • intrinsic (related to the inherent properties of the phagocyte)
  • extrinsic (due to other factors).
23
Q

What are phagocytic intrinsic disorders related to?

A

• different stages of phagocyte differentiation and function have been identified
o stem cell differentiation
o chemoattraction
o intracellular killing of the microbe

24
Q

What are phagocytic extrinsic defects related to?

A
  • 1) deficiency of antibody or complement

* 2) suppression of phagocytic activity (e.g., by glucocorticoids).

25
Q

What is Cyclic Neutropenia?

A
  • Stem cell differentiation leading to neutropenia: too few neutrophils
  • very low neutrophil count for 3 to 6 days of a 21 day cycle.
  • The molecular mechanisms are unclear.
26
Q

What is Leukocyte Adhesion Deficiency (LAD)? What causes LAD1? What causes LAD2?

A

• Lack of adhesion to endothelium.
• LAD1 is due to the absence of a beta-integrin resulting in the absence of LFA-1 expression.
• LAD2 is due to a defect in GDP-fucose transporter and results in no sialyl-Lewis X, which is a ligand for E-selectin.
o E-selectin is the initial attachment to the endothelium at sites of inflammation.

27
Q

What is Chediak-Higashi syndrome? What phagocytes are affected?

A
  • Defective phagocytosis: phagosomes do not fuse with lysosomes.
  • affects macrophages and NK cells
28
Q

What is Chronic Granulomatous Disease (CGD)?

A
  • defect in NADPH oxidase, which results in defective intracellular killing of bacteria.
  • Often X-linked genes, so males will be affected at an early age.
  • Recurrent severe bacterial and fungal infections occurring at sites acting as environmental barriers:
  • Skin -Lymph nodes
  • Liver or spleen -
  • Lungs
  • Gastrointestinal tract
  • Infecting organisms are specifically ‘catalase positive.’ the faulty phagocyte cannot use the organism’s endogenously produced hydrogen peroxide to kill them.
  • Patients are no more susceptible to viral infection than anyone else.
29
Q

What is Interferon-gamma Receptor Deficiency?

A

• Defects in IFNγ responsiveness, such as, or defects in IL-12 or IL-12 receptors leads to atypical mycobacterial infections.

30
Q

What is Job’s Syndrome (also known as Hyper IgE Syndrome)

A

• a failure to produce IFN-γ by Th cells resulting in a reduced killing of bacteria by macrophages.

31
Q

Complement deficiencies

A
  • complement components and their inhibitors
  • If deficient in C3, prone to recurrent infections with both encapsulated organisms such as pneumococcus and streptococcus, as well as with Neisseria.
  • Deficiencies in the MAC complement components result in increased susceptibility to infections by meningococcus (e.g. Neisseria)
  • Deficiencies in the regulatory molecules result in increased inflammation
32
Q

What are Regulatory components complement deficiencies?

A
  • Hereditary angioedema

* Paroxysmal Nocturnal Haemoglobulinuria

33
Q

What is Hereditary angioedema

A
  • C1q inhibitor deficiency

* continuous complement activation and consumption.

34
Q

What is Paroxysmal Nocturnal Haemoglobulinuria?

A
  • Decay Accelerating Factor (DAF) deficiency
  • lysis of red blood cell precursors
  • a defect in the anchoring of DAF to the cell membrane.
35
Q

What are C1, C2, C4 complement deficiencies?

A
  • an immune complex disease because
  • unable to remove Ag-Ab complexes
  • This resembles systemic lupus erythematosus (SLE).
36
Q

What is a C3, factor H, factor I deficiency?

A
  • the most serious complement deficiency

* repeated infections with pyogenic bacteria

37
Q

What is a MAC (C5-9) deficiency?

A

• results in repeated infections with Neisseria bacteria species.

38
Q

Secondary immunodeficiencies

A
  • the most common form of immunodeficiency

* occur due to some external factor, such as infection, chemotherapy, or nutrition status.

39
Q

(1) Excessive loss of immunoglobulins
① Protein-losing enteropathy
② Nephrotic syndrome
(2) Depression of the immune system by
① Old age ② Malnutrition ③ Leprosy ④ Malaria ⑤ Viral infections such as acquired immunodeficiency syndrome ⑥ Sarcoidosis ⑦ Surgery ⑧ Uraemia
(3) Immunosuppression by
① X-rays ② Corticosteroids ③ Cytotoxic drugs ④ Antilymphocyte serum ⑤ Antimetabolite drugs
(4) Neoplasia
① Hodgkin’s disease ② Multiple myeloma ③ Waldenstrom’s macroglobulinaemia ④ Chronic lymphatic leukaemia
(5) Splenectomy

A

(1) Excessive loss of immunoglobulins
① Protein-losing enteropathy
② Nephrotic syndrome
(2) Depression of the immune system by
① Old age ② Malnutrition ③ Leprosy ④ Malaria ⑤ Viral infections such as acquired immunodeficiency syndrome ⑥ Sarcoidosis ⑦ Surgery ⑧ Uraemia
(3) Immunosuppression by
① X-rays ② Corticosteroids ③ Cytotoxic drugs ④ Antilymphocyte serum ⑤ Antimetabolite drugs
(4) Neoplasia
① Hodgkin’s disease ② Multiple myeloma ③ Waldenstrom’s macroglobulinaemia ④ Chronic lymphatic leukaemia
(5) Splenectomy

40
Q

What is HIV and AIDS?

A

• caused by HIV-1 and HIV-2
• exhibits trophism for CD4+ cells
• It binds and gains entry into T cells and monocytes (the primary reservoir for the virus) through the CD4 molecule on these cells.
• Other accessory receptors (chemokine receptors) are involved in viral gp120 binding to T lymphocytes and monocytes.
• Individuals lacking functioning chemokine receptors do not progress from HIV infection to AIDS• AIDS is defined as allowing the occurrence of opportunistic infections
o (e.g. pneumocystis) or Kaposi’s sarcoma (caused by HHV8)
• This results from the loss of CD4+ helper cells
• Infection of monocytes and antigen presenting cells is also important in the speed of progression of the disease.

41
Q

What is Immune Senescence?

A
  • The effect of aging on immunity.
  • diminished heterogeneity and function of the T cell compartment
  • By age 60, thymus tissue is replaced by fat and we are dependent on T cells generated earlier in life.
  • The number of memory T cells [CD45R0+ T cells (memory phenotype)] increases, accumulate activated T cells, and limited numbers of naïve cells entering the pool.
  • In addition to a restricted TCR repertoire, the ability of old T cells to expand seems limited, since upon antigenic stimulation, ‘old’ T cells do not expand as effectively as young T cells.
42
Q

What are age-associated reductions in humoral immunity?

A
  • a change in the quality of the antibody response.
  • 1) decreased antibody specificities from foreign to autoantigens;
  • 2) shift of antibody isotypes from IgG to IgM;
  • 3) antibody affinities from high to low.
  • may be due to the impaired capacity of T cells to induce maturation of B cells.
  • a reduction in nascent B cell development in the bone marrow
43
Q

What are Therapy options and management?

A
  • Antibiotics and IVIg antibodies
  • IFN-γ injection may have some benefits (e.g. in Chronic Granulomatous Disease (CGD)).
  • Bone marrow transplants
  • gene therapy
  • Fetal liver and thymus grafts
44
Q

Antibiotics and antibodies. Antibiotic therapy is the standard treatment for bacterial infections. In some cases prophylactic antibiotics may be required. Children whose immune system produces no antibodies begin to experience recurrent infections after maternal antibody from placental transfer in utero is depleted. These individuals are treated with antibiotics and intravenously with periodic injections of pooled immunoglobulins (IVIG) from normal human serum. There are no good replacement therapies for cellular deficiencies, although bone marrow transplantation can be effective. In some cases, s.c. IFN-γ injection may have some benefits (e.g. in CGD).

A

Antibiotics and antibodies. Antibiotic therapy is the standard treatment for bacterial infections. In some cases prophylactic antibiotics may be required. Children whose immune system produces no antibodies begin to experience recurrent infections after maternal antibody from placental transfer in utero is depleted. These individuals are treated with antibiotics and intravenously with periodic injections of pooled immunoglobulins (IVIG) from normal human serum. There are no good replacement therapies for cellular deficiencies, although bone marrow transplantation can be effective. In some cases, s.c. IFN-γ injection may have some benefits (e.g. in CGD).

45
Q

Bone marrow transplants and gene therapy

A
  • when MHC compatible donors
  • mortality rate from an allogeneic bone marrow transplant can be very high (25% within the first 100 days of transplant).
  • reconstitution of normal phagocytic function in Chronic Granulomatous Disease (CGD)
  • Reconstitution of B and T cells in SCID
46
Q

Fetal liver and thymus grafts have also been used

o Graft Host problems
o In DiGeorge patients, there have been attempts to implant a thymus graft
gene therapy

A

Fetal liver and thymus grafts have also been used.
o Graft Host problems
o In DiGeorge patients, there have been attempts to implant a thymus graft
gene therapy