- only in males; no mature B cells

- defective B cell tyrosine kinase gene (X-LA gene)

- decreased Ig levels

- small/absent tonsils and lymph nodes

- major infections after 6-9 months

(Haemophilus influenzae, strep. pneuomoniae)

X-linked Infantile Agammaglobulinemia

(X-LA, Bruton's Disease)

- delay in the ability of B cells to produce IgG

- low IgG from lack of help from CD4+ T helper cells

- may persist up to 36 months

- treatment not usually given

Transient Hypogammaglobulinemia

- acquired onset of symptoms occurs 15-35 yrs

- B cells are present, do not differentiate

- do not secrete antibodies (division or not)

- IgG, IgA, IgM are deficient

- Decline in T cell function

- High frequency of autoimmune dx and malignancy

- frequent infections

- treatment: antibiotics, pooled IgG

Common Variable Hypogammaglobulinemia

- most common antibody deficiency

- failure in terminal differentiation of IgA-producing B cells

- recurrent sinopulmonary infections/chronic diarrhea

- autoimmune dx is common

- treatment: antibiotics

IgA Deficiency

- very rare

- Low IgG2 +/- IgG4 occurs in children

- Low IgG3 occurs in adults

- failure in terminal differentiation of IgG subclass

- Recurrent bacterial infections (ear, sinus, bronchial)

- Treatment: antibiotics, pooled IgG

IgG Subclass Deficiency

- B cells cannot switch from IgM

- related to mutated or deficient CD40-mediated T/B cell signaling

- High IgM

- IgM-producing plasmacytes infiltrate tissues

- liver abnormalities

- anti-neutrophil, anti-RBC

Immunodeficiency with High IgM (HIGM)

- variable degree of deficiency

- "interference" in pharyngeal pouches 3/4

- "no" T cells, thymus, parathyroid

- facial, heart, blood vessel malformations

- majority have learning disabilities

- Frequent infections: Candida albicans, pneumocystis jirovecii, viral infections

- treatment: transplantation of fetal thymus, cardiac surgery, Ca supplement

Congenital Thymis Aplasia (DiGeorge Syndrome)

- chronic infection of skin and mucus membranes with Candida

- involves selective T cell defect

- normal T cell and B cell response to everything but Candida

- Treatment: antifungal drugs

Chronic Mucocutaneous Candidiasis

- "Bubble Boy" disease

- defective lymphoid stem cells (no T or B cells)

- live vaccines can be rapidly fatal

- skin rash common

- treatment: bone marrow transplant

Severe Combined Immunodeficiency Disease (SCID)

- X chromosome that codes for y chain of IL-2 receptor

- Also for IL-4, 7, 11, 15, 21

X-linked SCID

- ATP and dATP accumulate to toxic levels in lymphoid stem cells

Adenosine deaminase (ADA) enzyme deficiency

- Lack of HLA class I, II

- mutations are in genes that code for a transporter protein (class I), transcription (class II)

Bare lymphocyte syndrome

- most severe form of SCID

- from developmental arrest of precursor cells at very early stage

- lymphocytes, granulocytes, monocytes are deficient

- death within a few weeks

Reticular dysgenesis

- due to mutations in gene encoding WASP

- IgM level is low, high IgA

- T cell count may be normal, but declines with age

- thrombocytopenia, abnormal platelets, bleeding, eczema

treatment: antibiotics, antivirals, steroids

Wiskott-Aldrich Syndrome (WAS)

- slowly progressive disease

- defective ATM gene that assists in DNA repair

- mutations in TCR genes, Heavy chain genes

- IgA is low

- high incidence of lymphoma/leukemia

- severe cerebellar ataxia (muscle incoordination)

- "spider-like" enlargement of blood vessels (eyes)

treatment: supportive care, pooled IgG

- neutrophils, monocytes, macrophages are deficient

- mutations in genes --> NADPH oxidase activity

- results in granulomatous abscesses (lung, liver, LNs)

- susceptible to bacterial/fungal infections

- Treatment: broad-spectrum, antifungal, abscess drainage, bone marrow transplant, IF-y1b

- neutrophils, monocytes, macrophages are deficient

- low level of enzymes in large granules

- killing of phagocytic cells delayed

- low killing by NK and T cytotoxic cells

- albinism, photophobia, rapid involuntary eye movements, CNS abnormalities

- Treatment: antibiotics, bone marrow transplant

Chediak-Higashi Syndrome

- most common type of infection with C3, C5-9 complement deficiencies

- Ex: Neisseria meningitides

Gram-negative bacterial

- fails to inhibit C1qrs activation and factor XII/kallikrein

- results in increased vascular permeability

- swelling, skin/mucus membranes

- cramps, nausea, vomiting, diarrhea, laryngeal swelling

- no increase in infections

Prophylais: C1-inhibitor

Hereditary Angioedema

- Poor nutrition (outside US)

- Immunosuppressive drugs for malignant dx's, transplantation, autoimmune dx, allergies (in US)

- Protein loss (enteropathies, nephrotic syndrome, burns)

- Infections (AIDS, cytomegalovirus, Epstein-Barr, Rubella, Mycobacterium TB, and M. leprae)

- DM, liver dx, alcohol abuse, Uremia, anesthetic agents, radiation, lymphoproliferative disorders, splenectomy

Causes of Secondary Immunodeficiencies

- frequent or unusual infections, eczema, growth retardation, developmental defects

- CBC w/ 3-part diff

- ELISA test for HIV-1 proteins

- Skin tests for hypersensitivity

- Levels of Anti-A/B, IgM, IgG, IgA

- Hemolytic complement evaluation

Screening for Immune Competence

- Chest x-ray for thymus

- Quantify lymphocytes w/ antibodies against CD3,4,8

- LN biopsy

- transformation of mitogens test

- stimulation of alloantigens

- cytokine production

T Cell evaluations

- Antibody titers before and after specific immunization

- Quantification of IgG subclasses

- Count peripheral lymphs that express Ig for Fc/EBV

- LN biopsy

- transformation with mitogens

B Cell (Antibody) Evaluations

- oxygen radical production by neutrophils (Nitroblue Tetrazolium test)

- Quantify specific complement components

- Test for monocyte chemotaxis

- Presence of specific intracellular enzymes

- Quantitative test of bacterial killing (opsonization)

Phagocytes and Complement Testing