Immunodeficiency disease

Secondary immunodeficiencies (9) are much more common than primary ones and frequently occur as a result of immaturity of the immune system in premature infants, immunosuppressive therapy, or surgery and trauma. Illnesses, particularly when prolonged and serious, have been associated with secondary immunodeficiencies, some of which may be reversible. Acquked immune deficiency syndrome (AIDS) (10—12) may be considered a secondary immunodeficiency disease caused by the human immunodeficiency vimses HIV-1 or HIV-2. Hitherto unknown, the disease began to spread in the United States during the latter part of the 1970s. The agent responsible for this infection has been isolated and identified as a retrovims. 

Adenosine deaminase deficiency is associated with an immunodeficiency disease in which both thymus-derived lymphocytes (T cells) and bone marrow-derived lymphocytes (B cells) are sparse and dysfunctional. Purine nucleoside phosphorylase deficiency is associated with a severe deficiency of T cells but apparently normal B cell function. Immune dysfunctions appear to result from accumulation of dGTP and dATP, which inhibit ribonucleotide reductase and thereby deplete cells of DNA precursors. 

Lekstrom-Hunes JA, Gallin Jl Immunodeficiency diseases caused by defects in granulocytes. N Engl J Med 2000 343 1703-... 

Hernandez PA, Gorlin RJ, Lukens JN, et al. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat Genet 2003 34 70-4. 

Low levels or absence of adenosine deaminase (ADA) is associated with one form of severe combined immunodeficiency disease (SCID) characterized by B-andT-lymphocyte dysfunction due to toxic effects of deoxyadenosine (HI9). Most patients present as infants with failure to thrive, repeated infections, severe lymphopenia, and defective cellular and humoral immunity. Disease severity is correlated with the degree of deoxyadenosine nucleotide pool expansion and inactivation of S-adenosylhomocysteine hydrolase in red blood cells. Up to now, more than 40 mutations have been identified (A4, H20, S5, S6). The majority of the basic molecular defects underlying ADA deficiency of all clinical phenotypes are missense mutations. Nonsense mutations, deletions ranging from very large to single nucleotides, and splicing mutations have also been reported. It is likely that severe... 

H4. Hershfield, M. S., and Mitchell, B. S., Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. In Metabolic and Molecular Bases of Inherited Disease, 7th ed. (C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, eds.), pp. 1725-1768. McGraw-Hill, New York, 1995. 

In addition, we discuss the most likely clinical consequences of mild-to moderate immunosuppression and potential confounders as well as non-immune factors that may modify these disease outcomes. Cases of profound immunosuppression, such as primary immunodeficiency diseases or HIV/AIDS, are not discussed, as these represent extreme examples of immunosuppression where neither the specific clinical diseases nor the eventual outcomes have much in common with events that occur in individuals with mild-to-moderate immunosuppression. 

In contrast to profound immunosuppression, such as that which occurs in patients with HIV/AIDS or primary immunodeficiency diseases, exposure to immunotoxic chemicals or drugs is believed to be more likely to cause mild-to-moderate levels of immunosuppression (e.g., a 20% decrease in white blood cell counts). This review attempts to address, both qualitatively and quantitatively, the potential adverse health effects of moderate levels of immunosuppression. The following general conclusions can be surmised. 

Considerable data is available suggesting thatmild-to-moderate immunosuppression can lead to an increase in infectious disease. The types of infections that occur tend to result from either common pathogens (e.g., causing upper respiratory tract infections) or latent viruses (e.g., herpes cold sores), rather than opportunistic organisms such as Pnuemocyctis carinii. These are usually not life-threatening, except in certain susceptible populations, such as the elderly. Opportunistic infections, in contrast, are more prevalent in individuals where severe forms of immunosuppression are present, such as primary immunodeficiency diseases or HIV/AIDS. 

Examples of the early application of recombinant DNA technology in medicine are the development of recombinant human growth hormone human insulin human interferons, thought to have anticancer activity in addition to antiviral activity interleukins (regulatory proteins from lymphocytes that are believed to be important in the treatment of immunodeficiency diseases and cancer) tumor necrosis factor epidermal and bone marrow progenitor cell growth factors and the production of vaccines (Table 12.1). 

Down-modulation of the immune response (immunosuppression), which may result in an impaired ability to deal with neoplasia and infections. This is of particular concern if the therapeutic agent is intended to be used in patients with preexisting conditions such as cancer, severe infection, or immunodeficiency diseases. 

Currently, there is stUl a gap for the potential of gene therapy to be fulfilled. Gene therapy clinical trials have been conducted for diseases such as severe combined immunodeficiency disease (SCID, bubble baby syndrome), sickle cell anemia, cystic fibrosis, familial hypercholesterolemia, and Gaucher disease. 

SCIDGeneTherapy Trial Infantswithsevere combined immunodeficiency disease (SCID, bubble boy syndrome) have a gene defect that leads to a complete lack of white blood cells. Without treatment, these infants die from comphcations of infectious diseases during the first few years of life. The only treatment currently approved for this condition is a bone marrow transplant. 

Severe combined immunodeficiency disease The enzyme adenosine deaminase degrades deoxyadenosine which is produced during DNA degradation (Chapter 10). Deficiency of the enzyme results in accumulation of deoxyadenosine which is a substrate for adenosine kinase and leads to production of deoxyadenosine and deoxyquanosine triphosphates, which reach high concentrations. This disturbs the balance of deoxy nucleotides which results in failure of DNA replication. This enzyme is normally present in lymphocytes so that a deficiency prevents proliferation of the lymphocytes, which is essential in combatting an infection. Consequently, patients are very susceptible to infections. This is one disease that is effectively treated by gene therapy. 

The human immunodeficiency virus (HIV) causes the immunodeficiency disease known as AIDS (acquired immune deficiency syndrome). The structure of this virus is similar to that of the influenza virus (A). 

Familial hypercholesterolemia Severe combined immunodeficiency diseases... 

Immunoglobulin obtained from pooled plasma obtained from hepatitis B and HIV negative donors is used as an aspecific immunostimulant in immunodeficiency diseases, idiopathic thrombocytopenia, autoimmune hemolytic anemias, Kawasaki syndrome and to prevent infections in immune compromised patients with leukemia or multiple myeloma. Adverse effects include potentially severe hypersensitivity reactions. 

Primary immunodeficiency diseases (PIDs) are defects of the immune system that are due to genetic abnormalities or some failure in normal embryological development. They are usually apparent at birth or develop shortly thereafter. Approximately 70 PIDs have been described, including those specihc for humoral immunity (e.g., X-linked agammaglobulinemia, immune globulin [Ig] A dehciency), cellular immunity (e.g., DiGeorge s syndrome), or both (e.g., severe combined immunodehciency syndrome). 

D) A primary immunodeficiency disease that is blocking the maturation of B cells into plasma cells... 

D. The boy has significantly reduced serum antibody levels and a reduced ability to mount an antibody response to childhood vaccinations. The most probably cause is a primary immunodeficiency disease affecting humoral immunity. 

Unlabeled Uses Asthma, chemotherapy-induced stomatitis, dermographia, familial immunodeficiency disease, malaria, mastocytosis, Meniere s disease, nausea, neuro-cysticercosis, otitis media, psoriasis, radiocontrast media reactions, urticaria... 

Keerthikumar, S., Raju, R., Kandasamy, K., Hijikata, A., Ramabadran, S., Balakrishnan, L., Ahmed, M., Rani, S., Selvan, L.D.N., Somanathan, D.S., et al, (2008) RAPID Resource of Asian Primary Immunodeficiency Diseases. Nucl Acids Res, 37, D863-D867. 

H. Other considerations Proleukin has been designated an orphan drug for use in the treatment of metastatic renal cell carcinoma, metastatic melanoma, non-Hodgkin s lymphoma, and primary immunodeficiency disease associated with T-cell defects. 

Indications Enzyme replacement therapy for adenosine deaminase (ADA) deficiency in patients with severe combined immunodeficiency disease (SCID) who are not suitable candidates for—or who have failed— bone marrow transplantation... 

E. Therapeutic response Adagen has been effective in reversing biochemical abnormalities in children with adenosine deaminase deficiency and severe combined immunodeficiency disease (SCID). It is... 

Dunbar, C., L. Chang, C. Mullen, et al.. Amendment to Clinical Research Project. Project 90-C-195. April 1,1993. Treatment of severe combined immunodeficiency disease (SCID) due to adenosine deaminase deficiency with autologous lymphocytes transduced with a human ADA gene. Hum Gene Ther, 1999.10(3) 477-88. 

AIDS represents the classic example of immunodeficiency disease caused by extrinsic factors, in this instance the human immunodeficiency virus (HIV). This virus exhibits a strong tropism for CD4 T helper cells these become depleted, giving rise to increased frequency of opportunistic infections and malignancies in infected individuals. AIDS is also characterized by an imbalance in THl and TH2 cells, and the ratios of cells and their functions are skewed toward TH2. This results in hypergammaglobulinemia, loss of cytotoxic lymphocyte activity, and delayed hypersensitivity. 

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