Immunology IV. IMMUNODEFICIENCIES

IMMUNODEFICIENCIES

A. Primary immunodeficiencies are inherited or congenital, and are generally rare.

1. Phagocytic cell defects. Patients with defects in phagocytic cells have frequent bacterial infections.

a. Chronic granulomatous disease (CGD) is a group of disorders that involves the inheritance of defects in the NADPH (nicotinamide adenine dinucleotide phosphate) oxidase, which is essential for the production of the reactive oxygen species during the respiratory burst that accompanies phagocyte activation. Patients with CGD experience severe recurrent bacterial and fungal infections, often resulting in the formation of granulomas that can obstruct the gastrointestinal and urogenital systems. Early diagnosis and treatment, typically with prophylactic antibacterial and antifungal agents, as well as administration of IFN-g, can be effective, although at present, the only long-term cure is allogenic hematopoetic cell transplant (bone marrow transplantation).

b. Leukocyte adhesion deficiency (LAD) is a group of rare inherited disorders that is due to a defect in adhesion molecules of neutrophils, and often other leukocytes, that are necessary for leukocytes to enter the tissue from the blood. LAD patients should receive early antimicrobial therapy; allogenic hematopoietic stem cell transplantation has been successful in many LAD patients.

2. Complement system deficiencies

a. Complement component C3 is common to all pathways of complement activation, and as such, deficiencies in C3 have the most dramatic effect. Patients with C3 deficiency suffer from recurrent, and often severe, bacterial infections involving the upper respiratory tract, meninges, and bloodstream. Patients lacking the fluid phase control proteins (factor H and factor I) experience a similar pattern of recurrent infections due to the uncontrolled activation and thus depletion of C3.

b. Patients with immunodeficiencies in the lectin pathway of complement activation experience recurrent bacterial infections, typically in early childhood, prior to establishing an efficient antibody repertoire.

c. Lacking the early components of the classical pathway leads to an increase in the incidence of immune complex diseases and some autoimmune diseases, such as systemic lupus erythematosus and glomerulonephritis.

d. Patients lacking the late-acting complement components (C6–C9) are unable to form the MAC (Complement membrane attack complex); however, they are competent for opsonic function, immune clearance, and initiating inflammation via the complement cascade. Lacking any of these terminal complement components increases the patient’s susceptibility to infections with Neisseria.

e. Treatment. Complement deficiencies that lead to recurrent bacterial infections should be managed with antimicrobial therapy. Supplementation with purified complement components has had some success, although the half-life of most complement components is short, and frequent infusions would be required.

3. Antibody-related deficiencies

a. X-linked agammaglobulinemia (XLA) is due to mutations in the Bruton tyrosine kinase gene, which is important for BCR (B-cell receptor) signaling. XLA patients lack mature B cells, plasma cells, and all five classes of antibody. Patients with XLA have recurrent infections usually beginning at 5 to 6 months of age, when maternal antibody transferred prior to birth is waning. Treatment involves antimicrobial therapy as well as periodic injections of intravenous immunoglobulin containing large amounts of IgG.

b. Selective IgA deficiency is the most common primary immunodeficiency disorder and is characterized by a reduced level of IgA in the presence of normal levels of the other antibody isotypes. Many patients are asymptomatic or experience a slight increase in the frequency of respiratory tract infections. The genetic basis for selective IgA deficiency is not yet defined and is likely to be a heterogeneous group of genetic abnormalities. The foundation of treatment for IgA deficiency is the treatment of the associated infections, and no specific immunotherapy is required.

c. X-linked hyper-IgM (XHIM) syndrome is characterized by high levels of serum IgM and very low levels of serum IgG, IgA, and IgE. The B cells from these patients are functionally normal; however, their T-helper cells lack a ligand (CD40 ligand) that is important for signaling to the B cells to undergo isotype switching and generate memory B cells. The CD40 ligand is also important for T-cell interaction with dendritic cells and macrophages. XHIM presents with recurrent bacterial infections; some patients also have recurrent neutropenia and anemia. It is important to treat the associated bacterial infections; the infusion of immunoglobulin for intravenous use (IVIG) is the traditional therapy. Bone marrow transplantation can be performed in certain situations and will reconstitute the immune system with functional T cells, thereby improving antibody and leukocyte function.

4. T-cell–associated immunodeficiencies

a. DiGeorge syndrome or congenital thymic aplasia is a T-cell deficiency that is due to the failure of the thymus to develop normally during embryogenesis. Cell-mediated immune responses are undetectable in DiGeorge patients, and they present with multiple recurrent or chronic infections with viruses, bacteria, fungi, and protozoa. Additional features of DiGeorge patients include cardiac anomalies, renal anomalies, eye anomalies, hypoparathyroidism, and skeletal defects. Patients with partial hypoplasia often recover thymic function and need no immunologic treatment. Transplantation of postnatal allogeneic cultured thymus tissue has successfully reconstituted immune function in DiGeorge patients with severe T-cell deficiency.

b. Severe combined immunodeficiency (SCID) is a phenotypic term for a wide range of congenital and inherited immunologic defects that include the loss of both B- and T-cell systems. Most patients experience severe, recurrent infections that begin in the first few months of life. Some of the genetic defects result in defective T-cell signaling through cytokine receptor mutations or kinases involved in cytokine signaling (JAK3 kinase). Still other defects are in genes important for TCR complex signaling (CD3) or genes encoding recombinase enzymes required for gene rearrangement in TCR and BCR generation. Mutations in genes that control class II MHC expression result in a condition known as bare lymphocyte syndrome, which functionally presents as SCID, because class II MHC expression is necessary for TH cell development in the thymus. Most SCID patients will not survive the first year of life unless the immune system is reconstituted by hematopoietic stem cell transplantation.

B. Secondary immunodeficiencies. Defects in immunity that are secondary to another cause are more common than primary causes.

1. Malnutrition is the most common cause of immunodeficiency disorders worldwide, and malnourished individuals often experience an increased incidence of infectious diseases, an impaired response to vaccination, defects in cell-mediated immunity, and defective phagocyte function, all of which reverse following adequate nutritional support.

2. Patients with lymphoproliferative diseases, such as leukemia and myeloma, are also prone to infection. These patients experience varying degrees of hypogammaglobulinemia and impaired antibody responses; some lymphoproliferative diseases also lead to defective cell-mediated immune function.

3. In developed countries, immunodeficiency is often due to specific medical treatment. Therapeutic agents such as x-rays, cytotoxic drugs, and corticosteroids can have dramatic effects on the immune system. Immunosuppressive drugs, such as used to prevent organ transplant rejection or used to suppress autoimmune reactions, can also affect lymphocyte and neutrophil activity.

4. Some microorganisms suppress the immune response, particularly cytomegalovirus, measles, rubella, Epstein-Barr virus, and some bacterial infections, such as tuberculosis, leprosy, and syphilis.

5. AIDS is a late stage of a progressive infection with HIV. HIV (either HIV-1 or HIV-2, although HIV-1 is more common in the United States) selectively infects CD4-bearing cells leading to a gradual depletion of TH cells. AIDS is defined by the presence of certain opportunistic infections and cancers including Pneumocystis pneumonia; disseminated cryptococcosis; histoplasmosis; toxoplasmosis; mycobacterial disease; persistent, ulcerative herpes simplex virus infection; Kaposi sarcoma; and disseminated cytomegalovirus infection. 

There are many specific targets for antiretroviral therapy, including reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, and fusion inhibitors (reviewed more specifically later). Early intervention using a combination of drugs, while monitoring CD41 cell count and viral load, allows for tailored treatment regimens to achieve the best results for individual patients (i.e., highly active antiretroviral therapy or HAART). There are no known cures and no effective vaccines available for HIV, although there are clinical vaccine trials ongoing.

Ref: Comprehensive Pharmacy Review

http://en.wikipedia.org/wiki/Chronic_granulomatous_disease
http://en.wikipedia.org/wiki/Leukocyte_adhesion_deficiency
http://ghr.nlm.nih.gov/condition/x-linked-hyper-igm-syndrome

Some pictures in this article are found by google search;
http://www.immunopaedia.org.za/fileadmin/gallery/Chronic%20Granulomatous%20Disease/chronicgranulomatousdisease1.jpg
http://www.nejm.org/na101/home/literatum/publisher/mms/journals/content/nejm/2012/nejm_2012.367.issue-8/nejmicm1106350/production/images/large/nejmicm1106350_f1.jpeg
http://www.ladinfo.org/Adhesion.jpg
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