Primary Immunodeficiencies

Question 1

Bruton’s X-linked agammaglobulinemia

Answer 1

• Inheritance pattern: *X-linked (occurs solely in males) - Age of symptom onset: *5-6months - Major clinical manifestations: *Otitis media *Bronchitis *Septicemia *Pneumonia *Arthritis *Meningitis *Dermatitis - Primary underlying immunologic defect: Inability of pro- and/or pre-B cells to develop into mature B cells *Maturation blocked after rearrangement of the heavy chain gene *Due to absence of required tyrosine kinase *Important for transducing signals from the BCR that trigger differentiaton - Severe depression or virtual absence of all classes of immunoglobulin - Near absence of mature B cells in blood, bone marrow, spleen, lymph nodes

Question 2

Selective IgA deficiency

Answer 2

• Inheritance pattern: *Autosomal dominant or recessive, some occur after infection (toxoplasmosis, measles, others?) - Major clinical manifestations: variable *Most are asymptomatic *Some repeated GI and respiratory infections *GI infections less common b/c of better cooking, processing *Immune complex disease, higher incidence of allergy and autoimmune disorder - Primary underlying immunologic defect: *Failure of terminal differentiation to IgA-secreting plasma cells *Some also lack IgG2 and IgG4 *In some cases assoc. w/defects in receptor for cytokine involved B cell activation (BAFF)

Question 3

IgG and IgA deficiency with increased IgM (hyper-IgM syndrome)

Answer 3

• Inheritance pattern: *X-linked (70%) - Major clinical manifestations: *Severe bacterial infections, pneumocystis - Primary underlying immunologic defect: *Failure of heavy chain class switching *T cells cannot activate macrophages via CD40:CD40L; impaired resistance to intracellular microbes *Make only IgM; many are autoantibodies against blood cells; leads to secondary immunodeficiency *Deficient in their ability to make IgA, IgG and IgE

Question 4

Common variable immunodeficiency

Answer 4

• Inheritance pattern: *Sporadic, sometimes inherited - Age of symptom onset: *childhood/adolescence - Major clinical manifestations: variable *Increased infection by pyogenic organisms (sinopulmonary) *Giardia *Sometimes recurrent herpes *High incidence of autoimmune phenomena (RA) *High incidence of malignancies (lymphoid, gastric) - Primary underlying immunologic defect: *Intrinsic B cell defects *Abnormalities in T cell activation *Causes unknown in majority of cases

Question 5

DiGeorge Syndrome (thymic hypoplasia)

Answer 5

• Inheritance pattern: *Defective development of the third and fourth pharyngeal pouches *Most are sporadic *Deletion in chromosome 22 *Some assoc. w/maternal alcohol consumption *Rarely: autosomal dominant or translocations involving chromosome 22 - Age of symptom onset: *Newborns - Major clinical manifestations: *Distinctive facial features: +eyes widely seperated +ears are low set +philtrum of the upper lip is shortened *Congenital malformations of the heart *Lack of thymus and parathyroids +coneonatal tetany +hypocalcemia - Primary underlying immunologic defect: *Absence of cell mediated immunity +low numbers of T cells in blood and lymphoid tissue +T cell zones depleted +paracortical area of lymph nodes +periarteriolar sheaths of spleen * Antibody levels low to normal +fail to mount specific antibody responses

Question 6

SCID caused by common gamma chain deficiency

Answer 6

• Inheritance pattern: *X-linked - Major clinical manifestations: *Low T cells *Antibody production very low b/c of lack of T cell help *NK cells also affected +IL-15 involved in maturation and proliferation - Primary underlying immunologic defect: *Common gamma chain deficiency (50-60%) *Gamma chain of IL-2R missing

Question 7

SCID: Adenosine deaminase deficiency

Answer 7

• Pattern of inheritance *Autosomal recessive - Major clinical manifestations: *Accumulation of deoxyadenosine and further metabolits - Primary underlying immunologic defect: *Toxic to rapidly dividing immature lymphocytes, especially those of T cell lineage *T cell numbers more affected than B cell numbers

Question 8

Other causes of autosomal recessive SCID

Answer 8

• Mutations in RAG genes - Blocks development of T and B lymphocytes - Mutations of the Jak3 protein kinase - Mutations in signaling molecules - Class II MHC mutations - Bare lymphocyte syndrome

Question 9

Wiscott-Aldrich syndrome

Answer 9

• Pattern of inheritance: *X-linked - Major clinical manifestations: *Thrombocytopenia *Eczema *Marked vulnerability to recurrent infection - Primary underlying immunologic defect: *Progressive depletion of T lymphocytes in peripheral blood and T cell areas of lymphoid organs +variable loss of CMI +antibody production impaired +antibody against polysaccharides absent, against proteins low +IgM low, IgG normal

Question 10

Inherited deficiencies of complement

Answer 10

• C3 *Increased susceptibility to serious, recurrent pyogenic infection *Immune complex glomerulonephritis - MAC components (C5-C9) *Increased incidence of Neisseria infection - C1 inhibitor: hereditary angioedema