Primary Immunodeficiency Diseases

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Signs of PIDs

- Ten or more new ear infections/year
- Family history of PIDs
- Failure to thrive (as energy is spent on fighting infection)
- Two or more serious sinus infections or pneumonias within a year
- Need for IV antibiotics to clear infection

Immunologic Signs of PIDs

- Below normal ELISA values for IgG/IgM and/or IgA.
- Abnormal T:B lymphocyte ratios, CD4:CD8 ratios or both.
- Diminished humoral immunity, cell-mediated immunity (CMI), or both against standard vaccines.

B Cell Deficiencies

Result in pyogenic bacterial infections (e.g., S. pneumoniae and H. influenza).

T Cell Deficiencies

Result in viral and other intracellular microbial infections (e.g., P. jiroveci, atypical mycobacteria, fungi).

Innate Immune Deficiencies

Infectious consequences vary, but pyogenic bacterial infections are common.

Four Major B Cell Deficiency Diseases

- IgA deficiency
- Common variable immunodeficiency (CVID)
- X-linked immunodeficiency with hyper-IgM syndrome
- X-linked agammaglobulinemia (XLA)

IgA Deficiency

- Most common immunodeficiency disease in Caucasians.
- Defined as the total absence or severe deficiency of IgA.
- Recurrent ear and/or respiratory infections, GI infections, dental caries and/or pneumonia.

Common Variable Immunodeficiency (CVID)

- Recurrent respiratory and GI tract infections after age 10 years and low to normal levels of IgM, with low IgG, and/or IgA (the most common presenting finding).
- Patients usually have normal B cells numbers, but have poor antibody responses to TD and/or TI antigens.
- Some degree of T lymphocyte dysfunction is present in up to 50% of patients.
- Mutations in many different genes may cause the pathologic phenotype.
- Treatment: IVIg is the treatment of choice.

X-linked Agammaglobulinemia (XLA)

- Characterized by the total lack of immunoglobulin, mature B cells, germinal centers in lymph nodes or spleen and patients lack tonsils and adenoids.
- Due to defect in the btk (tyrosine kinase) gene, which is necessary for B cell development.
- Diagnosis: Testing serum Ig levels. Patients show marked decreases or absences of ALL FIVE immunoglobulin classes.
- Antibody replacement through gamma globulin (IVIg) therapy.

X-linked Hyper-IgM Syndrome (HIGM)

- Class switch recombination defect.
- Characterized by severe, recurrent bacterial infections with decreased or absent levels of IgG, IgA and IgE, BUT ELEVATED IgM; serum IgM levels are markedly increased and may reach levels in excess of 1000mg/dL.
- Caused by a failure of class switching (66% of patients have a defect in CD40:CD40L interactions.
- Lymph nodes from patients with HIGM lack germinal centers
- Treatment: IvIg, as per XLA and CVID.

Severe Combined Immunodeficiencies (SCID)

- SCID affects both B and T cells
- Patients will have few, if any, T and B cells (lymphopenia), but normal numbers and function of NK cells and phagocytes (defects are in VDJ recombinase).
- No rearrangement of Ig or TcR genes.
- SCID is a pediatric emergency.
- Hemopoietic stem cells (HST) is the treatment of choice for most SCID or T cell defect diseases.
- Patients have short life-spans if no HST available.

Adenosine Deaminase Deficiency

- The most common form of SCID.
- Currently available therapeutic options include bone marrow transplantation (BMT), enzyme replacement therapy with bovine ADA, or hematopoietic stem cell gene therapy.

X-linked SCID

Defect is in the common cytokine γ chain (IL4, IL7 and IFNγ); cytokine signaling, crucial for lymphocyte development, is insufficient.

Autosomal Recessive SCID

Due to defects in proteins involved in VDJ rearrangement or T cell signal transduction. Defects cause an inability of T and B cells to develop.

Typical Infections in SCID Patients

- Herpes simplex virus
- Cytomegalovirus
- Mycobacteria spp.
- Cryptosporidiosis
- Candidiasis
- Pneumocystis jiroveci
- Toxoplasmosis (protozoal pathogen)

Classic T Cell Immunodeficiencies

- DiGeorge syndrome
- Wiskott-Aldrich syndrome

DiGeorge Syndrome

- Characterized by an underdeveloped or missing thymus.
- Typical genetic deffect: deletion of part 22q11.2 (thymic + parathyroid development)
- T cell immunity is mostly absent, while humoral immunity is defective: Patients have no/limited responses to TD antigens (vaccines, proteins antigens), but normal responses to TI antigens.
- Treatment: Thymic transplants are effective for complete thymic absence, as is HST.

Wiskott-Aldrich Syndrome

- X-linked, combined immunodeficiency, with poor response to TI-2 (polysaccharide) antigens, eczema and thrombocytopenia.
- Patients are often lymphopenic.
- Arises form mutations in the Wiskott-Aldrich Syndrome protein (WASp), a cytoplasmic protein that links signaling by TCR and integrins to actin polymerization. WASp is important in T cell migration, and for the function of Tregs, and in T cell apoptosis, two negative mechanisms of immune regulation that maintain tolerance.
- Recurrent sinopulmonary infections are common, as are autoimmune disorders.
- Treatment: BMT, IVIg.

Defects in DNA Repair

- All characterized by chromosomal breakage in the Ig and TcR loci and sensitivity to ionizing radiation.
- Affects humoral and cellular immunity.
- All predisposed to tumor development.

Ataxia-telangiectasia

- DNA repair defect
- Recurrent sinopulmonary infections
- Neuromotor dysfunction (ataxia) and progressive paralysis
- Telangiectasia (dilated ocular or cutaneous blood vessels)

Hyper-IgE Syndromes

HIES (Job's syndrome) is distinguished by eczematous dermatitis, recurrent bacterial skin abscesses, marked elevation of IgE level and recurrent bacterial pneumonia.

Complement Activation Diseases

- Immune complex disease
- Susceptibility to Neisseria (pyogenic infections)
- Hereditary angioneurotic edema (HANE)

HANE

A rare disorder characterized by recurrent episodes of painless angioedema w/o urticaria or pruritis.
- Caused by a deficiency of C1 Inhibitor (C1INH)
- Swelling is due to absence of inhibition of the plasma kinin forming cascade with liberation of bradykinin. C' activation is NOT responsible for the swelling.
- Treatment: Anti-fibrinolytic agents or replacement therapy.

Leukocyte Adhesion Deficiency

Trafficking defect.

Chediak-Higashi Disease

Defect in lysosomal fusion.

Chronic Granulomatous Disease

Defective respiratory burst.

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