Primary Immunodeficiency (1) PDF

WELCOME- BMS 545 IMMUNOLOGY NOVEMBER 13, 2024 ANNOUNCEMENTS  Office hours:  Tues. 4-5 pm (virtual)  Thurs. 4-5 pm (in-person)  DITKI due Friday 11/15 by 12:59 pm  Pathophysiology of HIV  Friday’s class is an asynchronous recording for Research Days (1-4 pm)  Don’t forget you ca...

WELCOME- BMS 545 IMMUNOLOGY NOVEMBER 13, 2024 ANNOUNCEMENTS  Office hours:  Tues. 4-5 pm (virtual)  Thurs. 4-5 pm (in-person)  DITKI due Friday 11/15 by 12:59 pm  Pathophysiology of HIV  Friday’s class is an asynchronous recording for Research Days (1-4 pm)  Don’t forget you can a bonus point for attending!  Maximum ONE bonus point towards homework per person!  THE REST OF THE SEMESTER (ALL MODULE 4)  11/13- Primary Immunodeficiency  11/15- Secondary Immunodeficiency (Asynchronous). Research Days 1-4 pm  11/18-Transplantation & Immune Pharmacotherapy  11/20-Transplantation & Immune Pharmacotherapy & Cancer  11/22- Cancer & Tumor Immunity  11/25- Hypersensitivity (Asynchronous- Enjoy Thanksgiving break)  11/27-11/29- Thanksgiving break  12/2- Autoimmune Disorders  12/4- “What’s Wrong with Me?” Case Study  12/6- Final Immunology debrief:The Well Patient  LEARNING OBJECTIVES  Define and compare & contrast primary and secondary immunodeficiencies  Identify & describe the 8 different primary immunodeficiency groupings  Where would a “novel” immunodeficiency disorder be grouped? (e.g. based on what aspect of the immune system it affects, what group would it be put in?  Describe the different cell lineages affected & how they are affected in each PIDD (primary immune deficiency disorder) group & the specific disorders we cover  Provide examples of each of the different cell lineages of PIDD, causes, & consequences  Identify the PIDD by signs, symptoms, clinical presentation, or genetics  Specific disorders covered: SCID & CID, ADA, TAP, DiGeorge, Wiskott-Aldrich,Ataxia telangiectasia, Selective IgA, Immune deficiency with hyper IgM, XLA, CGD, G6PD, C3 deficiency, C1/C2/C4 deficiency, CD59 deficiency, etc.  FAILURE OF THE IMMUNE SYSTEM = REDUCED ABILITY TO RESIST INFECTION  Immunodeficiencies- caused by defects in components of immune system 1. Primary immunodeficiency disease- disease in which there is a failure of immunological function due to defect in one or more genes encoding components of immune system; Usually genetic, but can be result of randomly occurring errors in development  Most become apparent ~6 months old, when maternally derived antibodies start to disappear  So diverse, the term “Inborn Error of Immunity” (IEI) is now being used to describe them 2. Secondary immune deficiencies- caused by environment; e.g. infection, therapeutic treatments, cancer, & malnutrition  May occur at any time of life, depending on when exposure to causative factor(s) occurs  BOTH characterized by recurrent or chronic infections, inability to clear infectious agents after standard antibiotic therapy, presence of unusual infectious agents  Inherited immunodeficiency diseases 13-9 Rare primary immunodeficiency diseases reveal how the human immune system works >100 have been identified in humans- specific defective genes have been identified in many of them Less rare than originally thought, & vary in rarity depending on disorder 13-10 Inherited immunodeficiency diseases are caused by dominant, recessive, or X-linked gene defects Figure 13.10 Primary immunodeficiency syndromes comprise eight functional groups  Group 1 Affecting cellular and humoral immunity  DEFECTS IN LYMPHOID LINEAGE  Result in defective function of both B AND T cell numbers, functions, or both (& may not be equal in B & T cells)  Example: Severe combined immunodeficiency (SCID)- GROUP of diseases caused by different defects in individual genes that have similar functional consequences  Classic example of defects in combined lymphocyte lineage  SCID-related defects may occur in genes:  That encode enzymes (RAG-1, RAG-2) responsible for rearrangements of DNA that produce variable regions of Igs & TCRs  For cytokine receptors & in cell-to-cell interaction molecules for lymphocyte activation Figure 13.16 Inheritance of adenosine deaminase (ADA) deficiency in a family  Adenosine deaminase deficiency (ADA deficiency)- metabolic immunodeficiency disorder that causes SCID  Caused by mutations in ADA gene  Accounts for ~10–15% of all cases of autosomal recessive forms of severe combined immunodeficiency (SCID) among non-inbred population  Both parents are healthy carriers having one functional (green) & one defective (red) copy of ADA gene  2 of 8 children inherited a defective copy of ADA gene from each parent *Males = squares; females = circles and have ADA deficiency (+)  Rest of children are either healthy carriers or did not inherit any defective copy of gene  DEFECTS IN T-CELLS- RESULTS IN ABNORMAL #S &/OR FUNCTION 1. Can affect either CD4+ or CD8+ T cells or both  Frequent/recurrent fungal infections suggest T-cell defect because DTH response is largely responsible for clearance of fungi 2. Mutation(s) occur in cells critical to development/ activation of T cells  Example: TAP deficiency (aka bare lymphocyte syndrome)- defects in Transporter associated with Antigen Presentation (TAP)  Impair loading of peptide fragments into MHC I in all nucleated cells & reduce # of MHC I molecules that reach cell surface  Reduced MHC I expression decreases # of functional CD8+ cells & can affect functions of NK cells (Or MHC II with CD4+ cells)  Example: DiGeorge syndrome- defects in thymic development may inhibit or prevent development & thymic education of T cells  Variable severity & may include malformations of aorta, face/jaw, & parathyroid glands  Symptoms + testing allow early detection & treatment at birth ***DiGeorge is actually classified under group 2 now, but for simplicity in learning, I’m keeping it here, just based on genes & classification it falls under CID now***  Group 2 Combined immunodeficiencies with associated or syndromic features 13-16 Defects in T-cell function underlie severe combined immunodeficiencies  COMBINED IMMUNODEFICIENCY DISORDERS  Wiskott-Aldrich- rare x-linked recessive immunodeficiency disorder resulting in abnormal immune function & reduced ability to form blood clots; life expectancy is 3.5 months without treatment  WATER:  Wiskott-Aldrich OR WAS gene mutation  Thrombocytopenia  Eczema  Recurrent bacterial infections  Ataxia telangiectasia- (aka Louis-Bar syndrome) rare inherited childhood neurological disorder that affects part of brain that controls motor movement & speech; increased risk of leukemia & chronic lung conditions  Ataxia “without coordination”  Telangiectasias are small, widened blood vessels on the skin  Most patients become wheelchair bound 10 y.o. & generally die in 20s or 30s due to malignancies or respiratory insufficiency  Group 3 Predominantly antibody deficiencies 13-12 Antibody deficiency leads to poor clearing of extracellular bacteria  DEFECTS IN B-CELLS  B-cell defects are responsible for majority (>80%) of human immunodeficiency diseases  Immunoglobulin levels are typically affected, but not necessarily B-cell #s  Can be abnormal production of 1+ Ig isotypes  T-cell #s & functions are typically normal  Example: Selective IgA deficiency- most common immunodeficiency ~1-2 /1000 ppl.  Multiple gene defects produce it & evidence some forms may involve defective isotype switch signaling from T cells  Normal levels of other isotypes & often have other immunologic disorders (e.g., allergy or autoimmunity)  Example: Immune deficiency with hyper-IgM- defect in CD40 ligand  Isotype switch does not occur normally & produce high levels of IgM but deficient in B cells that produce IgG, IgA, or IgE  Example: X-linked agammaglobulinemia (XLA) (next slide) Figure 13.12 In people with X-linked agammaglobulinemia (XLA), B cells do not develop beyond the pre-B-cell stage  In XLA, Bruton’s tyrosine kinase (BTK) is defective  B cells become arrested at pre-B-cell stage because pre-B- cell receptor cannot generate intracellular signals  BTK gene is located on long arm of the X chromosome  Most people with XLA are male because males have only 1 X chromosome & there is no BTK gene on Y chromosome  Heterozygous females are carriers of trait  During development, cells in females randomly inactivate one X chromosome  Consequently, ½ of developing B cells in a female carrier become arrested at pre-B-cell stage because those cells inactivated X chromosome with good copy of BTK  Other ½ of developing B cells become functional B cells because they inactivated X chromosome that has bad copy of BTK  Inherited immunodeficiency diseases 13-13 Diminished production of antibodies can also arise from inherited defects in T-cell help Because T-cell “help” is critical to activation of naïve & memory B cells, also cause abnormalities in B-cell # & IG production  Group 4 Diseases of immune dysregulation  Group 5 Congenital defects of phagocyte number, function, or both 13-15 Defects in phagocytes cause enhanced susceptibility to bacterial infection  DEFECTS IN PHAGOCYTES  Defects in phagocytic cells are significant because defects affect two major functions: 1. Ability to kill microbes (Phagocytes fail to destroy ingested microbes)  Examples: Chronic granulomatous disease (CGD) Interactions with other cell types  Example: G6PD deficiencies Figure 13.15 Genetic defects affecting phagocytes cause persistent bacterial infections Know CGD & G6PD, just couldn’t’ box them with their clinical effects without accidentally boxing MPOD G6PD DEFICIENCY AND “FAVISM”  https://www.youtube.com/watc h?v=9-gvnQfbrIA  Evolutionary response to malaria?  “Researchers found that children with the African variant of the G6PD had twice the resistance to P. falciparum, the most severe type of malaria, that children without the mutation had”  Die now vs. Die later  Group 6 Defects in intrinsic & innate immunity  Group 7 Autoinflammatory disorders  Group 8 Complement deficiencies 13-14 Complement defects impair antibody-mediated immunity and cause immune-complex disease  DEFECTS IN COMPLEMENT  Numerous gene defects involving complement components increase susceptibility to infection & sometimes to risk of autoimmune disorders  Defects in alternative pathway & mannose- binding lectin (MBL) pathways & components = increased susceptibility to bacterial infection  Defects in classical pathway (except for C3) are NOT associated with increased susceptibility to infection (except encapsulated bacteria)  MBL & alternative pathways can generate sufficient complement-mediated protection against infection, without classical pathway  DEFECTS IN COMPLEMENT  Example: C3 deficiency= severe problems with recurrent infection & with immune complex-mediated disease because of key role of C3 in all 3 complement pathways  Deficiencies in C1, C2, & C4 → inefficient clearance of immune complexes, increasing risk of type III hypersensitivity diseases & injury to kidneys, joints, skin, & blood vessels  Deficiencies in CD59 allow accumulation of complement complexes, including MAC, on host cell membranes with ensuing cell injury