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.
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)
- 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.
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
- Mycobacteria spp.
- Pneumocystis jiroveci
- Toxoplasmosis (protozoal pathogen)
- 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.
- 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.
- DNA repair defect
- Recurrent sinopulmonary infections
- Neuromotor dysfunction (ataxia) and progressive paralysis
- Telangiectasia (dilated ocular or cutaneous blood vessels)
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)
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.