Unit 1 Nature of the Immune System Part 7 Immunodeficiency Diseases

1. Unit 1 Nature of the Immune SystemPart 7 Immunodeficiency Diseases Terry Kotrla, MS, MT(ASCP)BB

2. Introduction • The body’s immune cells attack and kill what they see as foreign invaders, usually bacteria, viruses, and fungi. • Any defect in the immune system decreases a person's ability to fight infections. • A person with an immunodeficiency disorder may get more frequent infections, heal more slowly, and have a higher incidence of some cancers.

3. Immunodeficiency Disorder • Immunodeficiency (or immune deficiency) is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. • Immunodeficiency disorders are a group of disorders in which part of the immune system is missing or defective. • Causes the body's ability to fight infections to be impaired. • Person with an immunodeficiency disorder will have frequent infections that are generally more severe and last longer than usual.

4. Immunodeficiency Disorder • Defects can occur in any component of the immune system or in more than one component (combined immunodeficiency). • Different immunodeficiency diseases involve different components of the immune system. • The defects can be: • Inherited • present at birth (congenital) • acquired

5. Immune Deficiency • Any of the following parts of the immune system may be affected: • Humoral (adaptive) immunity – B cells • Cellular immunity – T cells (remember there are 3 different kinds!) • Innate immunity – natural body structures and functions. • More than 120 different congenital forms of immunodeficiency have been reported.

6. What Do I Need to Know? • For each deficiency discussed you must know: • The name of the disorder. • What part of the immune system is affected. • Brief description of the immune disorder.

7. Immune Deficiency Disease Classification • Four Classification • Humoral System Deficiencies (which cell will be affected?) • Cellular Immunity Deficiencies (which cell will be affected?) • Combined Deficiencies • Acquired Deficiencies

8. Humoral Deficiencies • Conditions which cause impairment of humoral immunity, which can lead to immunodeficiency. • Caused by failures of B cells, the plasma cells they differentiate into, or the antibody secreted by the plasma cells. • Associated with increased vulnerability to infection, but can be difficult to detect (or asymptomatic) in the absence of infection.

9. Humoral Deficiencies • Types we will discuss: • Agammaglobulinemia • X-Linked Bruton’s Agammaglobulinemia • IgA Deficiency • Common Variable Immunodeficiency

10. Agammaglobulinemias • Genetic defects in B-cell maturation or mutation leading to defective interaction between B- and T-cells. • Many types of deficiencies involving deficiency in one or more antibody classes. • Infant values different than adult, may have transient hypgammaglobulinemia.

11. X-Linked Bruton’s Agammaglobulinemia • Genetic – X-linked affects males exclusively. • Lack a specific type of B cell. • Exhibit deficiency of immunoglobulins of ALL classes. • Have NO plasma cells. • T-cells present in normal numbers and function. • Develop recurrent bacterial infections. • Treat with gammaglobulin as needed. • Diagnosed by serum protein electrophoresis and testing for the CD19 positive B cells in peripheral blood.

12. IgA Deficiency • Most common congenital immunodeficiency, 1:500. • Varying expressions of the disease and most are asymptomatic. • Symptoms include respiratory and GI tract infections. • Individuals who are IgA deficient may develop anti-IgA and may develop analphylactic shock during blood transfusion. • No real treatment. • Diagnosed by serum protein electrophoresis

13. Common Variable Immunodeficiency • Have normal number of B cells but do not develop into plasma cells. • Production of one or more of the immunoglobulin types is decreased and the antibody response to infections is impaired. • Generally develops around the age of 10-20. • Symptoms vary, may have frequent infections, and some also will experience anemia and rheumatoid arthritis. • Diagnosis of exclusion. • Treat with IV immunoglobulin.

14. Cellular Immunity Deficiencies • Cell-mediated immunity is an immune response that does not involve antibodies or complement but rather involves • Activation of macrophages, • natural killer cells (NK), • antigen-specific cytotoxic T-lymphocytes, and • the release of various cytokines in response to an antigen. • Cellular immunity deficiencies primarily involve problems with T-cells

15. DiGeorge Anomaly • T lymphocyte deficiency that starts during fetal development and is the result of a deletion in a particular chromosome. • Children with DiGeorge syndrome either do not have a thymus or have an underdeveloped thymus. • Thymus directs the production of T-lymphocytes, these patients have very low numbers of T-lymphocytes. • Susceptible to recurrent infections, particularly viral and fungal. • Usually have other abnormalities as well- low-set ears, a small receding jawbone, and wide-spaced eyes. • In some cases, no treatment is required for DiGeorge syndrome because T lymphocyte production improves, otherwise fetal thymus transplant or bone marrow transplant.

16. Combined Deficiencies • Combined immunodeficiencies (or combined immunity deficiency) are immunodeficiency disorders that involve multiple components of the immune system, including both Humoral immunity and Cell-mediated immunity. • Topics we will cover: • Severe Combined Immunodeficiency • Wiskott-Aldrich Syndrome • Ataxia-Telangiectasia

17. Severe Combined Immunodeficiency • AKA “Bubble Boy Syndrome” • Results in impaired humoral and cellular immune responses. • Caused by the defective development or function of BOTH T- and B-cells. • Usually recognized during the first year of life with infections by nearly any type of organism. • Tends to cause a fungal infection of the mouth (thrush), diarrhea, failure to thrive, and serious infections. • If not treated with a bone marrow transplant, a person with SCID will generally die from infections before age two.

18. Wiskott-Aldrich syndrome • Rare X-linked recessive disease characterized by eczema, thrombocytopenia, immune deficiency and bloody diarrhea (secondary to the thrombocytopenia). • Abnormalities in both humoral and cellular immunity. • Usually have low levels of IgM, normal IgG and IgA, increased IgE. • Platelets have short half life and are small – why will this affect bleeding time? • T-cells affected, B-cells not. • Immune deficiency leaves the body vulnerable to infection, may be serious infections such as pneumonia, meningitis, and sepsis. • Splenectomy can help with thrombocytopenia. • BMT or cord blood stem cell transplant.

19. Ataxia-Telangiectasia • Rare, neurodegenerative, autosomal-recessive disease that affects many parts of the body and causes severe disability. • Ataxia refers to poor coordination and telangiectasia to small dilated blood vessels, both are hallmarks of the disease. • Combined defect of cellular and humoral immunity. • Poor antibody response, IgG2, IgA and IgE low or absent. • Decreased T cells • Most individuals do not live long in to their 20's. • Only therapy is allogeneic BMT.

20. Defects of Neutrophil Function • A defect in the life cycle of neutrophils can compromise host defenses. • Defects in neutrophil functions will lead to inflammation and increased susceptibility to recurrent and severe bacterial and fungal infections.

21. Defects of Neutrophil Function • Chronic Granulomatus Disease • Other Microbicidal Defects • Leukocyte Adhesion Deficiency

22. Chronic Granulomatus Disease • X-lined or autosomal recessive. • Phagocytes (i.e., neutrophils, monocytes and macrophages) are unable to kill bacteria and fungi. • Require an enzyme to produce reactive oxygen to destroy ingested bacteria, a process known as the oxidative burst. • Recurrent suppurative infections which eventually are fatal in childhood although 50% live to adulthood.. • Treatment: granulocyte transfusions, cytokines or BMT

23. Defects of Neutrophil Function • Other microbicidal defects • Neutrophil G6PD deficiency leads to condition similar to CGD. • Myeloperoxidase deficiency – recurrent candidal infections • Leukocyte Adhesion Deficiency • CD18 deficiency leads to abnormal adhesion, motility, aggregation, chemotaxis and endocytosis. • Several molecular defects of leukocyte adhesion cause recurrent life-threatening infections. • Can cause delayed wound healing, chronic skin infections, intestinal and respiratory tract infections and periodontitis.

24. Acquired Immunodeficiency • Immune deficiency may be the result of external processes or diseases; • The resultant state is called "secondary" or "acquired“ immunodeficiency. • Common causes for secondary immunodeficiency are malnutrition, aging and particular medications such as chemotherapy, • Many specific diseases directly or indirectly impair the immune system and include • many types of cancer, particularly those of the bone marrow and blood cells • certain chronic infections. • acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV). HIV directly infects a small number of T helper cells, and also impairs other immune system responses indirectly

25. The End Of Part 7