Lecture 40 Primary Acquired Immuno Deficiencies PDF

Primary Immunodeficiencies II – Acquired Immunity Dr. Shannon Murray, MS PhD BMS 5308 Lecture #40 [email protected] Lecture Objectives • Differentiate between primary and secondary immunodeficiency disorders. • Recognize the existence of redundancies in the immune system and how they apply to m...

Primary Immunodeficiencies II – Acquired Immunity Dr. Shannon Murray, MS PhD BMS 5308 Lecture #40 [email protected] Lecture Objectives • Differentiate between primary and secondary immunodeficiency disorders. • Recognize the existence of redundancies in the immune system and how they apply to masking signs of immunodeficiency. • Define the term opportunistic infection and relate its significance in immunodeficiency disorders. • Infer the ten warning signs of primary immunodeficiency. • Identify primary immunodeficiencies that result from defects in B lymphocytes, T lymphocytes or a combination of both B and T lymphocytes. • Recognize the specific clinical presentation associated with each primary immunodeficiency. • Identify the genetic basis and mechanisms contributing to each primary immunodeficiency. • Assess available treatment options for each primary immunodeficiency. • Compare and contrast the different primary immunodeficiencies. Special Acknowledgement • Dr. Teresa Johnson has taught this course for many years, and I am using many of her images or slides in this presentation as well as some from Dr. Harsha Bhagtani. Dr. Johnson’s acknowledgement is below. • “This lecture has been given by Dr. Renee Prater to the OMS students for most of the 20 years that she taught at VCOM-VC. I acknowledge her collegiality and experience as I have used her slide set as inspiration for this lecture.” Reading References • Basic Immunology, 6th ed., Abbas, Lichtman, and Pillai – Chapter 12 – “Congenital (Primary) Immunodeficiencies" subsections "Defects in Lymphocyte Activation and Function" through "Therapy of Congenital Immunodeficiencies" • Cellular and Molecular Immunology, 10th ed., Abbas, Lichtman, and Pillai – Chapter 21 – “Severe Combined Immunodeficiency" through "Therapeutic Approaches for Primary Immunodeficiencies" sections • Immunology for Medical Students, 3rd ed., Helbert – Chapter 32 – “Primary Immunodeficiency" Immunodeficiencies • Immunodeficiency – condition in which one or more components of the immune system are not present and/or are not functioning properly • Two groups of immunodeficiencies ‒ Primary – genetic defect in gene(s) of immune system that often manifests in infancy or early childhood ‒ Secondary – an environmental factor that damages the immune system (e.g., infection, malnutrition, toxic exposure, drugs); most commonly present in adulthood; also called acquired immunodeficiency • Redundancies and “back-up” mechanisms can mask the impact of immunodeficiency for a time, making diagnosis difficult https://callisto.ggsrv.com/imgsrv/FastFetch/UBER1/9780684325194_00239 Impact of Immunodeficiencies on Health: B cell and T cell Deficiencies Have Different Presentations • Altered structure and function of various parts of immune system • Extent of alteration dependent upon specific defect • Most common functional impacts ‒ More susceptible to infections – both: o Strict pathogens – always cause disease o Opportunistic pathogens – can inhabit host without causing disease, but with alteration in balance will cause disease ‒ Increased development of cancer – many associated with viral infection, e.g., EBV, HPV Table 21-1 – Cellular and Molecular Immunology, 10th ed., 2022 Ten Warning Signs of Immunodeficiency https://www.semanticscholar.org/paper/Clinical-Predictors-of-Primary-Immunodeficiency-in-Reda-El-Ghoneimy/0446af7018ec07e18f8021e57f9955a5609204ee Primary Immunodeficiencies of Adaptive Immunity Have Different Consequences • Can have localized or systemic effects • Defect in T cell only, B cell only, or both can alter architecture of lymphoid organ as well as create susceptibility to particular sets of pathogens – it is all tied to specific function of the lymphocyte Figure 12-1, Basic Immunology, 6th ed., 2020 Primary Adaptive Immunodeficiencies Can Result from Genetic Defects in Lymphocyte Maturation Most Common Cause of Autosomal Recessive SCID = Adenosine Deaminase Deficiency Severe Combined Deficiency (SCID) = Affects both Cellular and Humoral Immunity T cell mediated w or w/o B cell defects Figure 21-1 – Cellular and Molecular Immunology, 10th ed., 2022 Primary Adaptive Immunodeficiencies Can Result from Genetic Defects in Lymphocyte Maturation & Signaling Common Variable Immunodeficiency (CVID) Figure 21-2, Cellular and Molecular Immunology, Abbas et. al., 10th ed., 2022 Defects in Lymphocyte Development Many are Severe Combined Deficiency (SCID) = Affects both Cellular and Humoral Immunity T cell mediated often with B cell defects Figure 21-1 – Cellular and Molecular Immunology, 10th ed., 2022 Figure 12-4, Basic Immunology, 6th ed., 2020 Defects in Lymphocyte Activation th ed., 2020 Immunology, FigureFigure 12-5A,12-5A, Basic Basic Immunology, 6th ed.,6 2020 Figure 12-5B, Basic Immunology, 6th ed., 2020 T or B cell Primary Deficiencies Often Present with Different Infection Susceptibility T cell or T & B cells Primary T Cell Immunodeficiencies T Cell Development and Immunodeficiencies https://www.nature.com/articles/gim20042 DiGeorge Syndrome • Genetic basis or mechanism ‒ Microdeletion of chromosome 22 ‒ Most frequently the region around involving 22q11.2 ‒ May be due to loss of T box-1 gene TBX1 ‒ Inhibits develop of thymus – full or partial hypoplasia ‒ Parathyroid and other structures and processes (e.g., calcium homeostasis) also affected, leading to non-immunologic disease presentations • Clinical presentation of the defect – CATCH-22 ‒ Cardiac abnormalities ‒ Abnormal facies ‒ Thymic aplasia ‒ Cleft palate ‒ Hypocalcemia/hypoparathyroidism ‒ 22q11.2 microdeletion • Treatment – can be treated with fetal thymic transplantation or bond marrow transplant, but often not done (see notes) https://media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnrdp.2015.71/MediaObjects/41572_2015_Article_BFnrdp201571_Fig1_HTML.jpg The Face of DiGeorge Syndrome • Varying degrees of clinical manifestation depending on how much of the thymus is missing • Embryologic malformation involving 3rd and/or 4th pharyngeal pouches and pharyngeal arches https://link.springer.com/article/10.1007/s10875-021-01059-7 https://d3i71xaburhd42.cloudfront.net/f6120f9b81278 d504259d52b063c42e6e2963742/5-Figure3-1.png https://image.shutterstock.com/imageillustration/thymic-aplasia-260nw-702450427.jpg Thymic Shadow and DiGeorge Syndrome Normal DiGeorge “Sail sign” https://media.memorang.com/images/d985f4d4-6841-4190-b8f2-e6a68227a19e.jpg The Immunology of DiGeorge Syndrome • Immunodeficiency ‒ T cells – reduced numbers o Can be modest reduction to complete absence ‒ B cells and antibodies o B cell numbers generally normal, but function can be compromised by low T cell numbers o Ab – variable depending on severity of defect; may be virtually normal, but may be reduced due to lack of T cell help (recall fate of T-indep vs T-dep Ags) • Clinical presentation – disease manifestations ‒ Increased susceptibility to viral infections (think CD8 and CD4 cells!) ‒ Increased susceptibility to mycobacterial and fungal infections (think NK T cells!) https://www.frontiersin.org/files/Articles/417059/fimmu-1000447-HTML/image_m/fimmu-10-00447-g007.jpg Hyper-IgE Syndrome (Job Syndrome) • Genetic basis or mechanism ‒ Autosomal dominant ‒ Mutation in STAT-3 which inhibits IL-17 production • Clinical presentation ‒ Affects males and females equally ‒ Characteristic anatomical features (face, skeleton) o Eczema o Retained primary teeth o Staph skin abscesses without inflammation (“cold abscess”) o Recurrent bacterial pneumonia ‒ Immunologic features o Reduced Th17 cells, and increased IgE and eosinophilia o Low levels of IFN-γ (interferes with mac killing) and IL-17 (impairs PMN chemotaxis) o Recurrent pulmonary and skin infections – bacterial, Candida spp. ‒ Non-infectious diseases – eczema • Treatment – chronic prophylactic antibiotics Mnemonic – Job’s FATE F – Facies (coarse) A – Abscesses (cold, non-inflamed) T – Teeth – retained primary E – IgE, eosinophilia, eczema The Faces of Hyper-IgE Syndrome https://www.nejm.org/na101/home/literatum/publisher/m ms/journals/content/nejm/1999/nejm_1999.340.issue9/nejm199903043400904/production/images/img_mediu m/nejm199903043400904_f2.jpeg https://onlinelibrary.wiley.com/cms/asset /597cfd56-33aa-41b2-b5e7672aa9fc7478/pai12512-fig-0001-m.jpg • • • • Facial asymmetry Broad nose Deep-set eyes Prominent forehead • Rough appearance with exaggerated pore size of facial skin https://www.medicaljournals.se/acta/html-editor/html-img/5449/5449_18138.png https://ars.elscdn.com/content/image/1-s2.0S0917239421000483-gr4.jpg https://els-jbs-prodcdn.jbs.elsevierhealth.com/cms/attachment/5a8 389fd-7859-4aae-8eb6-582f5b0a0c88/gr1.jpg Primary B Cell Immunodeficiencies B Cell Immunodeficiencies • • • • • Responsible for over 50% of all immune deficiencies Caused by defective B cell development…. ….Or defective immunoglobulin production Predisposes for recurrent pyogenic infections Types of B cell immunodeficiency disorders 1. X-linked or Bruton’s agammaglobulinemia 2. Selective IgA deficiency 3. Common variable immunodeficiency https://media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnri1713/MediaObjects/41577_2005_Article_BFnri1713_Fig2_HTML.jpg X-Linked Agammaglobinemia (XLA) • Most common immunodeficiency caused by block in B cell maturation • Originally called Bruton’s agammaglobinemia • Genetic basis ‒ Multiple mutations in Btk gene, a tyrosine kinase on X chromosome ‒ Recessive X-linked disease – so much higher prevalence in men ‒ Recall Btk kinase is normally activated by pre-B cell receptor to initiate signaling cascades that lead to survival, proliferation, and differentiation of pre-B cells (checkpoint #1) • Immunologic impact ‒ Normal numbers and functions of T cells ‒ Affected males have no or few circulating B cells ‒ Serum has no IgA, M, D, or E, and little IgG ‒ Pre-B cells do not mature to B or plasma cells ‒ Underdeveloped germinal centers in LN, tonsils, Peyer’s patch https://www.acerta-pharma.com/content/dam/opendigital/acerta-pharma/en/science/btk-moa.jpg Clinical Presentation of XLA • Diagnosed at 6 months postnatally → waning of maternal antibodies reveals inability of infant to make antibodies • Symptoms – pyogenic infections such as: – – – – Recurrent bacterial otitis media (H. influenzae) Bronchitis, pneumonia (S. pneumoniae) Diarrhea (enteroviruses) Septicemia, arthritis, meningitis, dermatitis • Treatment: intravenous gamma globulins and prophylactic antibiotics • Interesting side bar: ~25% of pts develop an autoimmune disease (most often arthritis). Does this suggest role for Btk signaling in establishing B cell tolerance?? https://www.epainassist.com/images/symptoms-of-agammaglobulinemia.jpg Selective IgA Deficiency • Most common 1° immunodeficiency, affecting about 1 in 700 • Genetic basis (see notes – review article) ‒ Most specific mutations are not known, but it is thought that multiple genetic mutations lead to deficiency • Clinical manifestations Selective IgA Deficiency Immunology Medbullets Step 1 ‒ No serum or secreted IgA is made, but all other Ig isotypes are present at normal levels ‒ Many individuals have no clinical symptoms ‒ When symptomatic disease occurs, patients have infections of sinuses, lungs, and intestines (i.e., mucosal surfaces) o Giardia duodenalis is often implicated in intestinal infections ‒ Most common clinical condition – an anaphylactic blood transfusion reaction o Thought to be the result anti-IgA antibodies that have developed in IgA-deficient pt ‒ Also have an association with allergic and autoimmune https://www.researchgate.net/publication/337468662/figure/tbl1/AS:869789228597250@1584385320665/Diseases-associated-with-selective-IgA-deficiency.png diseases; do not know why Combined Primary Immunodeficiencies Severe Combined Immunodeficiency Disorder (SCID) • Heterogeneous group of diseases, 1:50,000 frequency • Accounts for ~ 20% of all primary immunodeficiencies • Defective cell-mediated and humoral immunity • May involve defects in T cells, B cells, or both • May also inhibit NK cells, impacting innate immunity • However, even if T or B cells are present, they may not be functioning properly in SCID patients. • Most common infections in SCID patients: ‒ Cytomegalovirus, varicella zoster virus, P. jirovecii, Candida spp., Pseudomonas spp., and bacteria • Modified live virus vaccine = dangerous and potentially fatal https://images.ctfassets.net/uszvm6pv23md/31hxoficumslpbODqfn0sP/3dd3bae20f0226bd086fab798c3fd9ec/Image__Severe_Combined_Immunodeficiency__SCID__-_406 X-Linked Severe Combined Immunodeficiency or X-SCID • Most common form of SCID, 25-33% • Genetic basis – Caused by mutation in common γ (γc) chain, subunit in many cytokine receptors, encoded on X chromosome – Inhibits differentiation of pro-T and NK cells in bone marrow and thymus due to loss of IL-7and IL-15-mediated signaling • Clinical presentation – Affects only males – X-linked – Near complete absence of T and NK cells in blood and in lymph tissue – B cells present, but they are dysfunctional – Loss of cell-mediated and humoral immunity https://ars.els-cdn.com/content/image/3-s2.0-B9780123742797180038-f18003-01-9780123742797.jpg The Common γ (γc) Chain and X-SCID • With mutation in γc, SO MANY cytokine receptors are made non-functional • Results in loss of immunity at multiple different levels • Innate vs adaptive • Development vs activation vs effector functions • Underscores the depth and breadth of immune deficiency in these patients as well as the challenges in management and treatment • Also see suppl. slide https://www.ucl.ac.uk/immunity-transplantation/sites/immunity_transplantation/files/styles/large_image/public/499-hpv-burns-2.jpg?itok=L2kyKiCz Adenosine Deaminase (ADA) Deficiency • Genetic basis – Autosomal recessive mutation in adenosine deaminase (ADA), enzyme that breaks down purines – Without ADA activity, dATP accumulates in lymphoid precursor cells during hematopoiesis – Becomes toxic and prevents lymphocyte development – Very similar disease process with mutation in purine nucleotide phosphorylase (PNP) resulting in build-up of purines, dATP and dGTP • Clinical presentation – Absence of T and B cells → SCID – Symptoms o Lymphopenia o Opportunistic infections o Increased autoimmunity http://www.decodegenomics.com.pk/wp-content/uploads/2018/02/ada2.png Mutations in RAG1 and RAG2 • Autosomal recessive SCID • Two forms of disease – Amorphic mutation – complete loss of gene activity – With NO functional RAG1/2, no TCR or BCR arrangement occurs, so there are no T cells or B cells made – Hypomorphic mutation – a partial loss of gene activity, often due to missense mutations that reduce the levels of mRNA or of protein made, so there is less functional protein o Hypomorphic mutations in RAG1/RAG2 cause Omenn Syndrome o Other genes may be involved, e.g., ARTEMIS, AIRE • Immunologic impact – Small number of T cell precursors are made, but they expand to give normal number of T cells – just limited diversity of recognition – Reduced number of B cells The Presentation of Omenn Syndrome • Clinical presentation – GVHD or autoimmune diseaselike rather than increased susceptibility to infection • Most frequent presentations ‒ Desquamation – shed outer layers of skin ‒ Erythroderma (reddened skin) ‒ Chronic diarrhea ‒ Hepatosplenomegaly ‒ Leukocytosis, lymphadenopathy ‒ Persistent bacterial infections ‒ Elevated levels of IgE produced • Mechanism behind this excessive immune activation is not known, but it is postulated to be due to extremely low levels of Treg cells relative to numbers of effector T cells These pictures demonstrate desquamation and erythroderma Various SCID Gene Mutations & Their Effects on B, T & NK Cells Gene mutation T cell B cell NK cell Common γ chain deficiency (X-linked) - + - Adenosine deaminase deficiency - - - IL-7R α - + + JAK3 - + - CD3 δ - + + CD45 - + + RAG-1/RAG-2 (Omenn syndrome) - - + DCLRE 1 (Artemis deficiency) - - + Ligase 4 - - + • The two most common causes of SCID are mutations in the shared gamma chain of interleukin receptors (X-SCID) and adenosine deaminase (ADA) deficiency. • ADA deficiency commonly presents with recurrent viral, bacterial, fungal, and protozoal infections, along with chronic diarrhea and failure to thrive. SCID is considered a pediatric emergency; usually bone marrow transplantation is warranted. Resources: DynaMed – https://www.dynamed.com/condition/severe-combined-immunodeficiency-scid First Aid for the USMLE Step 1 2021, page 37, 98, 117, 433 Hyper-IgM Syndrome • Clinical presentation ‒ Several different disorders ‒ Common endpoint of failure of B cell to isotype switch, so make high levels of IgM, but little to no IgG, IgA, or IgE ‒ Recurrent pyogenic infections • Genetic basis or mechanism ‒ Most common form (~70%) is X-linked hyper-IgM syndrome https://i.ytimg.com/vi/UF6-4hG65YI/hqdefault.jpg https://www.youtube.com/watch?v=UF6-4hG65YI o Mutation in CD40L gene on X chromosome o T cells do not express a functional CD40L molecule, so CD4 T cells cannot supply costim help to B cells (T-dep Ag) or to macs o Defects in both humoral and phagocytic immune responses o Pts with X-linked form are very susceptible to infection with Pneumocystis jirovecii since the phagocytosed fungus cannot be destroyed by the macs without T cell help ‒ 2nd most common form – autosomal recessive o Mutation is in CD40 rather than CD40L o Same clinical phenotype TREC and Newborn Screening for PID “All US states now screen newborns with T-cell receptor excision circles (TREC) to assess for absent or dysfunctional T cells. Circles of DNA are normally created as T cells pass through the thymus and undergo rearrangement of their receptor genes, and the presence of these circles on TREC analysis provides a measure of T cell maturation. Absence of these circles on screening TREC analysis is a feature of SCID.” The Merck Manual, https://www.merckmanuals.com/professional/immunology-allergic-disorders/immunodeficiencydisorders/approach-to-the-patient-with-suspected-immunodeficiency • Recall T cell receptor excision circles or TRECs – the excised DNA that is removed during construction of TCRs by the process of somatic recombination? • TRECs are quantitated in the circulation of a newborn infant as a correlate of the amount of thymic T cell development has occurred. • Lots of TRECs, lots of TCRs made. Low levels of TRECs → much reduced T cell development, suggesting possible primary immunodeficiency. Primary Adaptive Immune Deficiency Presentations: General Themes T cell or T & B cells Comparing the Diseases Disease Mutation Immune Defect Presentation DiGeorge Syndrome Micro-deletion chrom. 22 Reduced thymus and T cells Recurrent viral infections, facial anomalies, cleft palate Hyper IgE Syndrome X-Linked agammaglobinemia Selective IgA deficiency X-Linked SCID ADA deficiency Omenn Syndrome Hyper IgM Syndrome Summary I • What are the key characteristics of primary immunodeficiency disorders? – Genetic alterations, so occur before birth and generally present in early life – Are very rare – Often present as increased susceptibility to infection and recurrent infection • For each disease, be able to identify: – The genetic defect or alteration – The impact of the genetic defect on the immune response – in terms of what changes from norm occur – Recognize any key non-immunologic diagnostic features of the disease – Recognize any unique anatomical features specific to the disease – The groups of pathogens or any specific pathogens to which the patients are more susceptible • Understand the principles of TREC screening in potential diagnosis of primary immunodeficiencies. Summary II – Comparing B Cell Immunodeficiencies https://o.quizlet.com/drzEKgxhV.2v-v4.6vY4kQ.png References • Basic Immunology, Abbas, Lichtman, and Pillai; 6th ed., 2020 • Cellular and Molecular Immunology, Abbas, Lichtman, and Pillai, 10th ed., 2022 • Immunology for Medical Students, Helbert, 3rd ed., 2017 • Journal articles and publications as noted at images on each slide • ComBank question bank at www.truelearn.com Board Question A 6-month-old male is brought to his pediatrician with severe pneumonia associated with bacteremia, frequent otitis media, a chronic cough, and congestion. Cultures reveal Streptococcus pneumoniae and Haemophilus influenzae type B. Biopsies reveal lymphoid tissues that lack germinal centers, and plasma cells are absent in bone marrow and the lamina propria of the gut. What is the most likely diagnosis? A. Severe combined immunodeficiency B. DiGeorge syndrome C. Common variable immunodeficiency D. Wiskott-Aldrich syndrome E. Bruton agammaglobulinemia ComBank Question A 3-year-old male is suspected of having an immunodeficiency. Over the past two years he has experienced multiple staphylococcal skin infections as well as pseudomonas pneumonia and invasive infection with candida. Workup is remarkable for an abnormal dihydrorhodamine test. By which of the following additional organisms is he most likely to be susceptible to becoming infected? A. Streptococcus pneumonia B. Serratia marcescens C. Bacillus cereus D. Legionella pneumophila ComBank Question A 9-month-old female presents with a recurring diaper rash. On physical examination, a white curd-like substance covering her oral cavity is noted. A cutaneous injection of Candida antigens produces no reaction at 48 hours. There is no evidence of invasive disease. Which condition is responsible for this patient’s presentation? A. Wiskott-Aldrich syndrome B. Leukocyte adhesion deficiency C. Hyper IgM syndrome D. Ataxia-telangiectasia E. Chronic mucocutaneous candidiasis SUPPLEMENTAL SLIDES T Cell Activation and Function and Immunodeficiencies * * • Many different possible mutations that would compromise activation or effector functions of T cells, leading to an immunodeficient state in the patient! • Note: some of these (see ) are T cell deficiencies since that is the genetic mutation. However, they tend to * be classified as a combined immunodeficiency since functionality of B cells is compromised. Underscores helper function of CD4 T cells Table 21-5 – Cellular and Molecular Immunology, 10 ed., 2022 th IL-12 Deficiency Genetic basis or mechanism • Mutation in gene(s) encoding proteins p35 and/or p40 that form functional IL-12 heterodimer • May also be mutations in: ‒ IL-12 receptor such that IL-12 cannot bind ‒ Elements of signaling cascade → STAT3 most documented https://upload.wikimedia.org/wiki pedia/commons/8/8f/Figure_1._I L-12-dependent_IFN-gammamediated_immunity_and_IL23_signalling_in_response_to_S almonella_infection_.png Immunologic impact – reduced cell-mediated immunity • Reduced activation of naive CD4 to CD4 Th1 cells and/or CD8 T cells (recall 3-signal hypothesis) • Therefore, reduced production of IFN-γ and then reduced cell-mediated immune responses (via T cell pathways or mac feedback amplification pathway) • Also, reduced CD4 T cell help to make T-dependent antibody responses Treatment – exogenous IFN-γ https://media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnri1001/MediaObjects/41577_2003_Article_BFnri1001_Fig3_HTML.gif MHC Class I Deficiency Genetic basis or mechanism • Also called “Bare Lymphocyte Syndrome 1” or BLS1; very rare • Mutation in transport-associated protein (TAP) ‒ Either TAP1 or TAP2 subunit ‒ Prevents peptide loading to MHC Class I molecule, little to no MHC Class I exported to cell surface ‒ End result → “bare surface” ‒ Leads to inability to activate CD8 T cells Clinical presentation • • • • Recurrent viral infection Normal DTH response Normal Ab levels Increased numbers of NK cells and of γδ T cells – trying to compensate for absence of CD8 https://media.springernature.com/m685/springer-static/image/art%3A10.1038%2Fnri3339/MediaObjects/41577_2012_Article_BFnri3339_Fig1_HTML.jpg MHC Class II Deficiency • Autosomal recessive disorder • Also called Bare Lymphocyte Syndrome II (BLS II) or just Bare Lymphocyte Syndrome • Genetic basis ‒ Mutations in transcription factors that regulate MHC Class II gene expression (CIITA, RFX5, RFXANK) ‒ Little to no MHC-II expressed on APCs, but MHC-I expressed at normal or slightly reduced levels. • Immunologic impact http://quest.nasa.gov/projects/flies/images/adaptive.jpg ‒ No MHC-II Ag presentation in thymus, so reduced number of mature CD4 T cells in periphery ‒ Surviving CD4 T cells have defective activation, so cannot provide help to B cells, CD8 cells, or macs • Clinical presentation ‒ Recurrent infections (particularly GI) ‒ No delayed type hypersensitivity response Common Variable Immunodeficiency (CVID) • Heterogeneous group of disorders • Genetic basis or mechanism ‒ Different defects in individual diseases ‒ Some known mutations – in receptors for B cell growth factors and in costimulatory molecules needed for T-B cell interaction ‒ Commonality – great decreases in serum levels of IgG, IgA, and sometimes IgM → plasma cells cannot mature • Clinical presentation ‒ Affects both sexes equally (contrast with XLA, slide 22) ‒ B cells and T cells present at normal numbers ‒ Low levels of IgG, IgA, and sometimes IgM ‒ Recurrent bacterial infections (e.g., streptococci) ‒ Do not make Ab responses to infections or to vaccines (e.g., DTaP, MMR) ‒ Also present with autoimmune diseases and lymphomas • Treatment – intravenous immunoglobulins (IVIG) and prophylactic antibiotics https://i.pinimg.com/originals/40/96/4c/40964c873a7c646e899573b140417e2a.jpg Cytokine Receptors Utilizing the γc There are a lot! This explains the high frequency and the diverse impacts of the immunodeficiency in X-linked agammaglobinemia (XLA). https://media.springernature.com/full/springer-static/image/art%3A10.1038%2F35105066/MediaObjects/41577_2001_Article_BFnri35105066_Fig1_HTML.gif Autosomal Recessive SCID • Other forms of SCID where mutated gene is encoded somewhere besides the X chromosome • Common genetic mutations – JAK3 – adaptor molecule used by the γc chain, so loss of JAK3 function results in identical clinical presentation as X-SCID because the γc chain subunit is present but is unable to signal – ADA – accounts for ~50% of autosomal recessive SCID cases – RAG1 or RAG2 mutations – less common, causing Omenn syndrome – And other genes….. https://ars.els-cdn.com/content/image/3-s2.0-B9780128167687000077-f07-02-9780128167687.jpg Transient Hypogammaglobulinemia • At age 5-6 months, maternal antibodies are waning while infant antibody production should be increasing. • Premature infants may not have yet acquired ability to synthesize Ig. • Usually, no treatment is necessary (see notes) Zap-70 Deficiency • Autosomal recessive mutations in ZAP 70 • Patients typically present in first 2 years with recurrent infections • Different from SCID because they have normal lymphocyte counts and detectable lymphoid tissues • Lab findings ‒ Normal to ↑ lymphocytes ‒ Low to absent CD8+ T cells Hereditary Ataxia Telangiectasia • Autosomal recessive • Genetic basis – mutation in ATM gene ‒ ATM mutations lead to improper repair of dsDNA breaks during VDJ somatic recombination and during isotype switching • Clinical presentation ‒ Altered gait = ataxia ‒ Vascular malformations = talangiectases ‒ Neurologic defects ‒ Increased incidence of tumors ‒ Immunodeficiency with immunologic impact o Variable severity o Both T and B cells impacted o Deficiency in IgA and IgG2a are most common humoral immune defects, but also have lower levels of IgE o Most common T cell impact – thymic hypoplasia Wiskott-Aldrich Syndrome • X-linked recessive immunodeficiency disorder • Genetic basis – defect in WAS protein (WASP) – Glycoprotein that regulates rearrangement of actin cytoskeleton – Hypothesized to play a role in formation of immune synapse and leukocyte trafficking – Expressed on all cells of hematopoietic origin, so involved in function of nearly every cell in the immune system • Therefore, diverse set of clinical presentations for the “immunodeficiency” aspect of WAS depending upon which combination of cells are affected and extent of the effect • Classic triad = thrombocytopenia, immunodeficiency, eczema Nature Reviews Immunology volume 10, pages182–192(2010) The Presentation of Wiskott-Aldrich Mnemonic = WA-TER Wiskott-Aldrich triad • Thrombocytopenia • Eczema • Recurrent bacterial infections Purpura • Immunologic impact ‒ T and B cells present, but do not function normally ‒ Primary impact – ineffective B cell response to T-indep. polysaccharide antigens, increasing susceptibility to encapsulated bacteria o Serum IgG normal, but IgM is low o Serum IgA and IgE are elevated ‒ Major impact – defective formation of immune synapse so have ineffective activation of T cell by APC ‒ Significant impact – impaired leukocyte trafficking • Clinical presentation Eczema ‒ Affects males more than females ‒ Symptoms: Recurrent bacterial infection o Severe eczema o Pyogenic infections, esp. encapsulated bacteria o Thrombocytopenia ‒ Autoimmune disease – hemolytic anemia, IBD, nephritis