IMMUNOL LECTURE 12: IMMUNODEFICIENCY DISORDERS Ourlad Alzeus G. Tantengco, MD, PhD| 3rd TERM | A.Y. 2022-2023 August 4, 2023 ● ● IMMUNODEFICIENCY Autoimmunity – system attacks host cells and tissues Immunodeficiency – system fails to protect ○ Primary immunodeficiency ■ Genetic or developmental defect ■ Caused by defects in virtually any gene involved in immune development or function, innate or adaptive, humoral, or cell mediated, plus genes not previously associated with immunity ○ Secondary immunodeficiency ■ Acquired immunodeficiency ■ Loss of immune function that results from exposure to an external agent, often an infection PRIMARY IMMUNODEFICIENCIES Most of these disorders are caused by defects in a single gene, and are extremely rare ● Vary in severity from mild to nearly fatal ● Loosely categorized as affecting either innate immunity or adaptive responses and are often grouped by the specific components of the immune system most affected *the earlier the mutation, the more severe the manifestation of the disease and most likely fatal ● ● Combined immunodeficiency ○ Diseases resulting from an absence of T cells or significantly impaired T cell function, combined with some disruption of antibody responses ● B-cell immunodeficiency ○ Range from absence of B cells, plasma cells, immunoglobulins to absence of only certain classes of Abs ○ Subject to bacterial infection but do well against viral since T-cell branch is okay ● T-cell immunodeficiency ○ Can affect both humoral and cell mediated ● Primary immunodeficiencies are often detected early in life *can manifest after birth or as early as 6 months SEVERE COMBINED IMMUNODEFICIENCY ● The most severe forms of CID ● These stem from genetic defects that lead to a virtual or absolute lack of functional T cells in the periphery ● Usually fatal at early years of life ○ Infant will have viral and fungal infections ○ Bacteria don’t show up until later because of placental transfer of Abs from mother ○ Chronic diarrhea, pneumonia, lesions ● Many genetic defects can contribute to SCID ○ Usually defects that target the early steps of hematopoiesis ● Molecular mechanisms that explain the occurrence of SCID ○ Defective cytokine signaling in T cell precursors, caused by mutations in certain cytokines, cytokine receptors, or regulatory molecules that control their expression *cytokines are needed for immune cells to mature ○ Premature death of the lymphoid lineage due to accumulation of toxic metabolites caused by defects in the purine metabolism pathways ○ Defective V(D)J rearrangement in developing lymphocytes, caused by mutations in the genes for RAG1 and RAG2, or other proteins involved in the rearrangement process ○ Disruptions in pre-TCR or TCR signaling during development, caused by mutations in tyrosine kinases, adapter molecules, downstream messengers, or transcription factors involved in TCR signaling 1 ● ● Adenosine deaminase (ADA) deficiency ○ ADA catalyzes conversion of adenosine or deoxyadenosine to inosine or deoxyinosine, respectively *these purines need to be metabolized or else they will be accumulated and eventually become toxic ○ Intracellular accumulation of toxic adenosine metabolites, which interferes with purine metabolism and DNA synthesis Reticular dysgenesis (RD) ○ Initial stages of hematopoietic stem cell development are blocked by defects in the adenylate kinase 2 gene (AK2), favoring apoptosis of myeloid and lymphoid precursors and resulting in severe reductions in circulating leukocytes MHC DEFECTS ● A failure to express MHC molecules can lead to general failures of immunity that resemble SCID without directly impacting lymphocytes themselves ● Bare-lymphocyte syndrome ○ Caused by mutation in the TAP genes which are vital to antigen processing and presentation by class I MHC molecules ○ Failure to train T cells correctly, it affects both B and T cells DIGEORGE SYNDROME ● Decreased or absent thymus ● Results from deletion of region on chromosome 22 in developing embryo, developmental anomaly ● Lowered T cell numbers, results in B cells not producing sufficient antibodies ● DGS patients present with symptoms of immunodeficiency, hypoparathyroidism, and congenital heart anomalies WISKOTT-ALDRICH SYNDROME ● X-linked disorder ○ Results in issues with cytoskeleton components in hematopoietic cells ● Clinical manifestations usually appear early in the first year of life, eczema and thrombocytopenia are both common *if platelet count is low, patient is prone to bleeding ● Humoral defects, including lower than normal levels of IgM, as well as impaired cell-mediated immunity, are also common features ● WAS patients often experience recurrent bacterial infections, especially by encapsulated ● Treated with passive antibodies or stem cell transfer ● Can result in fatal infection or lymphoid malignancy X-LINKED HYPER-IGM SYNDROME ● Deficiency of IgG, IgE, and IgA but elevated levels of IgM ● Defect in T cell surface CD40L ○ This is needed for interaction between TH and B cell for class switching for T dependent antigens ○ T independent antigens are not affected therefore there is production of IgM HYPER-IGE SYNDROME (JOB SYNDROME) ● Caused by an autosomal dominant mutation in the STAT3 gene ○ Its absence is thought to lead dysregulation of TH pathway development and may be the reason for overproduction of IgE ○ Depressed TH17 responses, which are important for clearance of fungal and extracellular bacterial infections, explain the susceptibility of these patients to C. albicans and S. aureus ● Skin abscesses, pneumonia, eczema, and facial abnormalities ● High # of eosinophils and IgE ○ But don’t show increased allergies 2 X-LINKED AGAMMAGLOBULINEMIA ● Bruton’s agammaglobulinemia ● Caused by a defect in Bruton’s tyrosine kinase, which is required for signal transduction through the BCR ○ B lymphocytes in these patients remain in the pre-B stage, with heavy chains rearranged but light chains in their germ-line configuration ● Low levels of IgG and absence of other classes ● Recurrent bacterial infections COMMON VARIABLE IMMUNODEFICIENCY ● Reduction in the levels of one or more antibody isotype and impaired b-cell responses to antigen, all with no other known cause ● Can manifest in childhood or later in life, when it is sometimes called late-onset hypogammaglobulinemia ● Inheritance can follow autosomal recessive or autosomal dominant patterns, although most cases are sporadic SELECTIVE IGA DEFICIENCY ● Most of these affected are asymptomatic (up to 70%), whereas others may suffer from an assortment of serious complications ● Problems such as intestinal malabsorption, allergic disease and autoimmune disorders can be associated with low IgA levels ● Inability of IgA-expressing B cells to undergo normal differentiation to the plasma cell stage *prone to recurrent respiratory, digestive or intestinal infections LEUKOCYTE ADHESION DEFICIENCY ● Integrin proteins needed for adhesion and cellular interaction ○ Defect limits recruitment of cells into areas of inflammation ● Causes susceptibility to infection with both grampositive and gram-negative bacteria as well as various fungi ● Impairment of adhesion of leukocytes to vascular endothelium limits recruitment of cells to sites of inflammation CHRONIC GRANULOMATOUS DISEASE ● Prototype of immunodeficiency that impacts phagocytic function and arises in at least two forms ○ X-linked form in about 70% of patients ○ Autosomal recessive from found in the rest ● Defect in the NADPH oxidative pathway by which phagocytes generate superoxide radicals and other reactive compounds that kill phagocytosed pathogens ● Infection by bacterial and fungal pathogens, as well as excessive inflammatory responses that lead to the formation of granulomas (a small mass of inflamed tissue) CHEDIAK-HIGASHI SYNDROME ● Autosomal recessive disease ● Phagocytes don't have ability to kill bacteria ○ Mutations in LYST gene that cause defects in the transport of proteins into lysosomes as well as for controlling lysosome size, movement and function ○ Affected phagocytes produce giant granules, a diagnostic hallmark, but are unable to kill engulfed pathogens ● Neutropenia as well as impairments in T cells, NK cells, and granulocytes MENDELIAN SUSCEPTIBILITY TO MYCOBACTERIAL DISEASES ● Autosomal recessive trait – results from inbreeding *recessive trait in the family manifests in inbreeding ● Associated with defects in either the IFN-γ pathway (e.g., IFNγR or the related STAT signaling molecule) or IL-12/23 signaling pathway (e.g., IL-12, IL-12R, an the associated TYL2 signaling molecule) ○ These pathways are particularly important for clearing intravesicular infections *Important in killing engulfed bacteria *patients more susceptible to tuberculosis REDUCTION IN NEUTROPHIL COUNT ● Low concentration – granulocytopenia or neutropenia ● Congenital neutropenia ○ Frequent bacterial infections ● Acquired neutropenia ○ Certain drugs or chemotherapy can cause this ○ Autoimmune disorder – destruction of neutrophils *prone to infections COMPLEMENT DEFICIENCIES ● Fairly common ● Mostly associated with bacterial infections or immune-complex diseases ○ Deficiency in properdin, which stabilizes the C3 convertase in the alternative pathway, is 3 associated with increased risk of infection with species of Neisseria ■ These types of bacterial infection are also more common in those with defects in C5-C9 ○ Defects in mannose binding lectin (MBL) result in an increased susceptibility to a variety of infections by bacterial or fungal agents *patients are prone to meningitis ● ● ● ● ● TREATMENTS FOR IMMUNODEFICIENCIES Replacement of missing protein ○ Administering immunoglobulin ○ Express genes in vitro (in bacteria) for cytokines Replacement of missing cell type ○ Bone marrow transplantation Replacement of missing or defective gene ○ Gene therapy ■ Still far out from clinical use ■ Can be corrected in vitro and then introduce cells back into patient ACQUIRED IMMUNODEFICIENCY No genetic component Examples: ○ Hypogammaglobulinemia – unknown cause, different from genetic condition ○ AIDS caused by HIV ○ Malnutrition ● gp120 determines viral tropism by binding to target cell receptors, while gp41 mediates fusion between viral and cellular membranes *the cost of attachment (gp120) is always greater than the cost of fusion/penetration (gp41) ● Recognizes CD4 antigen on T cell ● ● HIV genotypes ○ HIV1 – main causative agent for AIDS ■ Many different subtypes ■ Probably evolved from Simian immunodeficiency virus and transferred to humans during the “bushmeat trade” in early 1900s ○ HIV-2 – cousin to HIV1 but diseases progresses slowly, if at all The typical course of an HIV infection SEVERE MALNUTRITION ● Affects both innate and adaptive immunity ● Sustained periods with very low protein-calorie diets (hypoproteinemia) are associated with depression in T-cell numbers and function, although deleterious b cell effects may take longer to appear ● Insufficiency in micronutrients, such as zinc, ascorbic acid, likely contributes to the general immunodeficiency and increases susceptibility to opportunistic infection THE GLOBAL AIDS EPIDEMIC *acute phase: fever, respiratory infection and will get better *as virus continues to proliferate it impairs CD4 T cells *prone to a lot of opportunistic infections *takes a long time for AIDS to manifest ● HIV treatment HIV EPIDEMIC IN THE PHILIPPINES *remember common suffixes HIV ● Retrovirus (Lentavirus genus) *army that reverse transcribe its RNA to DNA and will be incorporated in the host’s DNA ● Viral envelope derives from host ○ Can have class I or class II MHC 4