Disorders of Immunity Immunodeficiency Diseases

Objectives. Define immunodeficiency. Differentiate between primary and secondary immunodeficiency. List and understand the causes of Pr. Immunodeficiency. List and understand the causes of Secondary Immunodeficiency.

Origins of Immunodeficiency Immunodeficiency diseases are conditions where the defense mechanisms of the host are impaired Primary or Congenital Inherited genetic defects in immune cell development or function, or Inherited deficiency in a particular immune molecule Secondary or acquired A loss of previously functional immunity due to infection, toxicity, radiation, splenectomy, aging, malnutrition, etc.

Classification of Primary Immune Deficiency Syndromes Disorders of Phagocytosis Chr. Granulomatous Disease Myeloperoxidase Deficiency Chediac- Higashi Syndrome Leucocyte G6PD Deficiency Job’s Syndrome Tuftsin deficiency Lazy Leucocyte Syndrome Hyper IgE Syndrome Actin binding protein deficiency Shwachman’s disease Disorders of Specific Immunity Disorders of Complement Component deficiencies Inhibitor deficiencies Combined Immuno Deficiencies B & T Cell Defects Humoral Immuno Deficiencies B Cell Defects Cellular Immuno Deficiencies T Cell Defects

Immunodeficiency Diseases Patient unable to fight off infection Hall marks Repeated infections Opportunistic infections Increased susceptibility to tumors

Immunodeficiency Diseases Most are defects in T cells or B cells T cells, Macrophage defects = Fungal, Viral, protozoal infections B cells, Complement defects = Bacterial infections

Immunodeficiency Diseases Congenital Acquired

These immunodeficiency diseases may involve Specific immune functions like: Humoral immunity. Cell mediated immunity. Both. Or Non-specific mechanisms like: Phagocytosis. Complement.

Humoral immunodeficiencies – B cell defects. X- linked agammaglobulinemia. Transient hypogammaglobulinemia of infancy. Common variable immunodeficiency. Selective immunoglobulin deficiencies. Immunodeficiency with hyper IgM. Transcobalamin II Deficiency.

Cellular immunodeficiency – T cell defects. Thymic hypoplasia – DiGeorges Syndrome. Purine nucleoside phosphorylase (PNP) deficiency.

Combined immunodeficiency – Both B cell and T cell defects.) Cellular immunodeficiency with abnormal immunoglobulin synthesis – (Nezelof’s syndrome.) Ataxia telangiectasia. Wiskott- Aldrich Syndrome. Immunodeficiency with Thymoma. Severe combined immunodeficiency. MHC Class II deficiency.

Disorders of Complement. Complement component deficiencies. Complement inhibitor deficiencies.

Disorders of Phagocytosis. Chronic granulomatous disease. Myeloperoxidase deficiency. Chediak-Higashi syndrome. Leucocyte G-6-PD deficiency.

B- CELL DEFECIENCY X-Linked Agammaglobulinemia – Bruton’s disease. First immunodeficiency disease to be recognised. A.k.a Bruton’s disease. Basic defect is in failure of pre-B cells to differentiate into B cells. All classes of immunoglobulins are grossly depleted in the serum. B-cells in circulation decreased.

Tonsils, adenoids, lymph nodes are atrophic. Manifestations are not apparent till 6 months of age - ??? Patients suffer from recurrent infections with pyogenic bacteria – Pneumococci, Streptococci, meningococci, Pseudomonas and Hemophilus influenzae. T cells are normal hence can handle Viral, fungal and protozoal diseases.

Common variable immunodefeciency. A.k.a LATE ONSET HYPOGAMMAGLOBULINEMIA. Seen between 15-35 yrs of age. Characterized by recurrent pyogenic infections. B-cells normal in number but defective in function. Increased suppressor T cell and decreased Helper T cell activity.

Selective Immunoglobulin deficiency. Selective deficiency of one or more immunoglobulin class. Other classes normal. Selective IgA deficiency: Total absence of serum and secretory IgA. Increased susceptibility to respiratory and GIT Infections. Anti-IgA antibodies are found. Selective IgM deficiency: Assos with septicemia with meningococci and Gram Negative bacteria.

Immunodeficiency with Hyper IgM. Low levels of IgA, IgG with elevated IgM. X-Linked or autosomal reccessive. Patients are susceptible to infections and autoimmune disorders such as thrombocytopenia, neutropenia and hemolytic anemia--??

Cellular Immunodeficiency – T cell defects. Thymic Hypoplasia – DiGeorges Syndrome. Developmental defect of the 3rd and 4th pharyngeal pouches. Aplasia or hypoplasia of thymus and parathyroid glands. T-cells are deficient or absent in circulation. Humoral immunity –normal. Patients show enhanced susceptibility to viral, fungal and bacterial infections. Delayed hypersensitivity and graft rejection are depressed.

Combined immunodeficiency Both B cell and T cell deficincies. Nezelof’s Syndrome- Cellular immunodeficiency with abnormal immunoglobulin synthesis. Depressed CMI. Selectively elevated, decreased or normal immunoglobulins. Pts susceptible to viral, fungal and bacterial infections. Thymus is small and peripheral lymphoid tissues are atrophic. Autoimmune conditions like hemolytic anemia are common.

ATAXIA TELANGIECTASIA Autosomal recessive genetic disorder. Defeciency of cellular and humoral mechanisms. Assos. With cerebellar ataxia and dilated capillaries (telagiectasia), ovarian dysgenesis and chromosomal abnormalities. Most patients lack IgA and IgE. Death occurs due to sino-pulmonary infection in early life or malignancy in the 3rd decade.?? There is impairment of delayed hypersensitivity and graft rejection.

WISKOTT-ALDRICH SYNDROME X-linked reccessive disease. Characterised by eczema(elevated IgE), bleeding(thrombocytopenia) and recurrent infections. Most affected children die due to bleeding, infection or lymphoreticular malignancy.

SCID --Severe combined immunodeficiency diseases. These include many syndromes with severe combined deficiency of both humoral and CMI. They are inherited as AUTOSOMAL RECESSIVE MODE. There are 3 types of SCID

Swiss type of agammaglobulinemia. Cause is lymphoid stem cell defects. Absent humoral and CMI. Agammaglobulinemia and lymphocytopenia. Reticular dysgenesis. Most serious type of SCID. Defect at the level of multi-potent stem cell of bone marrow. Failure of myelopoeisis. Neutropenia, thrombocytopenia, anemia and bone marrow aplasia. Fatal in 1st week of life.

Adenosine deaminase deficiency: In these pts ADA is deficient in all tissues including RBC’s. ADA deficiency leads to accumulation of adenosine and deoxy adenosine triphosphate which are toxic to lymphocytes especially T cells. Great loss of T cell function as compared to B cell function. Vulnerable to all types of infections.

Complement deficiencies. Usually due to genetic abnormalities: C3 Def – pyogenic infections. C6, C7, C8 – Neisserial infections. COMPLEMENT INHIBITOR DEFICIENCY: C1 Inhibitor deficiency – hereditary angioneurotic edema.

Phagocyte Deficiencies Chronic Granulomatous Disease – NADPH oxidase defect Chediak -Higashi Syndrome – Abnormal lysosome formation Leukocyte Adhesion Deficiency – Absence of leukocyte adhesion molecules

Immunodeficiency Primary Immunodeficiency Secondary Immunodeficiency Neutrophil defects: CGD Humoral: B cell defects Humoral: Complement Cell-mediated: T cells Severe combined immunodeficiency Secondary Immunodeficiency AIDS Neutropenia Post-transplant BMT chemotherapy Splenectomised patient Malnutrition. Anti-cancer chemotherapy. Radiation therapy.

Primary Immunodeficiency Pathogens Humoral defects Capsulated bacteria S. pneumoniae H. influenzae N. meningitidis S. aureus Enteroviruses mycoplasma Cell-mediated intracellular bacteria Mycobacteria, Salmonella, Listeria, Legionella Viruses Herpes, Respiratory & Enteric viruses Fungi & protozoa Candida, Aspergillus, Pneumocystis, Cryptococcus, Cryptosporidium, Toxoplasma Neutrophil defects S. aureus, Candida, Aspergillus

Immune Deficiency Therapies B-cell deficiency : Gamma globulin SCID : Bone marrow transplant, enzyme replacement DiGeorge’s Syndrome : Fetal thymus transplant Gene therapy

Inherited Functional Disorders Disorders of Granulocyte Function Job’s syndrome – directional motility is impaired – recurrent boils and abscesses Lazy Leukocyte Syndrome – random and directed movement are defective – cells fail to respond to inflammatory stimuli – mild symptoms of low grade fever, recurrent infections (gums, mouth, ears) Chediak-Higashi – abnormal granule release

Inherited Functional Disorders Congenital C3 deficiency – inability to ingest microorganisms- repeated severe infections with encapsulated bacteria Chronic Granulomatous Disease – inability to kill catalase positive organisms – recurrent pyogenic infection Leukocyte Glucose-6-Phosphate Dehydrogenase Deficiency – similar to CGD Myeloperoxidase Deficiency-benign – slow bacterial killing, but complete

Monocyte-Macrophage Disorders Mucopolysaccharidoses – deficiencies in specific enzymes to degrade mucopolysaccharides (Hurley syndrome, Hunter syndrome: gargoylism) Lipidoses: lipid storage diseases – macrophages become overloaded with lipids (Gaucher, Niemann-Pick, Tay-Sachs)