Define Primary and secondary immunodeficiency
- 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.
What are the four components of immunodeficiencies?
- T cells
- B cells
- Phagocytes and Complement
What do T cell deficiencies predispose you to?
What about the B Cells, Phagocyte, and complement deficiencies?
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 do you evaluate antibody mediated immunity deficiencies?
- serum immunoelectrophoresis
- quantitation of immunoglobulins in serum and secretions
- detection of specific antibodies
a) Schick test - for IgG diphtheria anti-toxin
b) specific antibody responses - before and after immunization with killed vaccines - quantitation of circulating B-cells by flow cytometry with mAbs to surface Ig
- induction of B-lymphocyte differentiation in vitro
- lymph node biopsy
Evaluation of cell-mediated immunity
- DTH skin tests to common antigens - candida, streptokinase, streptodornase 6
- total lymphocyte count: 60-80% of peripheral blood lymphocytes are T-cells.
- enumerate T-cells and T cell subpopulations using mAbs to CD3, CD4 and CD8
- lymphocyte proliferation to lectins (PHA) and alloantigens – Mixed Lymphocyte Reaction
- in vitro analysis of T-lymphocyte function: production: IFNγ, IL-2; cellular cytotoxicity
Evaluation of phagocyte function
- total granulocyte and monocyte count
- chemotaxis assay - Boyden chamber
- assay for phagocytosis using opsonized particles and for bacterial killing
- test for superoxide generation using nitroblue tetrazolium (NBT) reduction
- assay for individual enzymes and for cytokines (IL-1 and IL-12)
- response to activation by cytokines (IFNγ, GM-CSF)
- Antigen processing and presentation
Evaluation of the complement system
- total hemolytic complement assay - CH50 a functional assay
- immunoassay of individual complement components
- neutrophil chemotaxis assay using C in patient’s serum as a chemoattractant
Antibody and B cell deficiencies
• 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
What is Bruton’s Disease?
• B cells fail to develop: congenital agammaglobulinaemia
What is X-linked agammaglobulinaemia? Are T cells normal?
• 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
What is Hyper-IgM syndrome?
- 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
What is Common Variable IgG/IgA Immunodeficiency (CVID)?
- 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.
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
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
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.
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.
What are the general traits of T cell deficiencies
- 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.
What is DiGeorge syndrome?
- due to an absent or very small thymus.
* severity depends on the amount of thymus present.
What is bare lymphocyte syndrome?
- 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
What is Wiskott-Aldrich syndrome (WAS)?
- a mutation in the WAS protein
* a T cell signaling pathway protein in cytoskeletal mechanisms for T cell activation
What is Ataxia-telangiectasia?
- 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.
What is Severe Combined ImmunoDeficiency (SCID)
• affects B cell and T cell development or function
What are some Stem cell defects in SCID?
• 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.
What are the two categories of phagocytic deficiencies?
- intrinsic (related to the inherent properties of the phagocyte)
- extrinsic (due to other factors).
What are phagocytic intrinsic disorders related to?
• different stages of phagocyte differentiation and function have been identified
o stem cell differentiation
o chemoattraction
o intracellular killing of the microbe
What are phagocytic extrinsic defects related to?
- 1) deficiency of antibody or complement
* 2) suppression of phagocytic activity (e.g., by glucocorticoids).
