Immunology Session 26 Primary Immunodeficiencies PDF

Immunology Session 26 Primary Immunodeficiencies Jeremy Ellermeier 360J Dobbelaere Hall 623-572-3687 Readings & Objectives - Immunodeficiencies ▪ Abbas Chapter 12 ▪ Compare and contrast primary and secondary immunodeficiencies Define primary and secondary immunodeficiency List the charact...

Immunology Session 26 Primary Immunodeficiencies Jeremy Ellermeier 360J Dobbelaere Hall 623-572-3687 Readings & Objectives - Immunodeficiencies ▪ Abbas Chapter 12 ▪ Compare and contrast primary and secondary immunodeficiencies Define primary and secondary immunodeficiency List the characteristics that may indicate an underlying immunodeficiency ▪ Understand each of the immunodeficiencies discussed including knowing: the nature of the specific deficiency (e.g., genetic mutation), if known what component(s) of the immune system are non-functional the effect on immune system function as a result of the deficiency Immunodeficiencies ▪ Primary Immunodeficiencies – caused by inherited genetic mutation Well over 100 have been described Effect immune cell development and/or function Theme: recurrent, sometimes overwhelming infections Focus for this lecture is less on individual diseases and more on how things can go wrong and how that effects immune function ▪ Secondary Immunodeficiencies – acquired by consequence of disease or environmental factor Malnutrition Chemotherapy HIV Primary Immunodeficiencies ▪ Murphy’s Law: Anything that can go wrong will go wrong And there are so many ways it can go wrong ▪ Genetically Inherited Generally recessive traits Often carried on the X chromosome Males have one X, so higher rates of disease Innate Immunity Deficiencies ▪ Complement Innate Immunity Deficiencies ▪ Complement ▪ C1s deficiency Renders classical complement pathway “dead” IgM/IgG do not activate complement Clearance of immune complexes impaired Innate Immunity Deficiencies ▪ C2 Deficiency Both Mannose and Classical pathways disrupted Susceptible to bacterial infections Often by normally non-pathogenic organisms Innate Immunity Deficiencies ▪ C3 Deficiency Autosomal recessive C3 mutation Patients create no detectable C3 Susceptible to array of bacterial infections, particularly Gram-negative bacteria Neisseria meningitidis, Enterobacter aerogenes, Haemophilus influenzae, and Escherichia coli Recurrent sepsis, pneumonia, wound infections 26% of patients develop immune complex- mediated autoimmune diseases resembling systemic lupus erythematosus 26% of patients develop glomerulonephritis, resulting in renal failure Innate Immunity Deficiencies ▪ C7 Deficiency Does not form MAC Lab mice show susceptibility only to certain Neisseria species Innate Immunity Deficiencies ▪ Complement Factor H competes with factor B for binding to C3b Has affinity to sialic acid on vertebrate cells Prevents complement activation on host cells Factor H deficiency Increased C3 & C5 convertase activity Excess complement activation leads to increased inflammation – Glomerulonephritis and renal failure can result Innate Immunity Deficiencies ▪ Complement Defects can occur in almost all of the complement components Similar outcomes: recurrent infections by extracellular bacterial pathogens that require opsonization for control Innate Immunity Deficiencies ▪ Leukocyte Adhesion Deficiencies (LADs) Deficiency in CD18 or β2 chain of LFA No adherence to endothelial cells Poor extravasation Leads to high WBC counts and recurrent infections – Often skin infections and ulcers – No or little pus at site of infection – Delayed umbilical stump separation » Inflammation at stump Journal of Clinical Neonatology. Vol. 3 Issue 2. April-June 2014 Innate Immunity Deficiencies ▪ Neutropenia Characterized by lower than normal neutrophil counts Severe congenital neutropenia Consistent counts lower than 0.5 x 109 neutrophils/liter of blood Caused by variety of mutations along development of neutrophils Frequent bacterial infections – Treated with aggressive antibiotic therapy and G-CSF Nat Rev Dis Primers 3, 17032 (2017). https://doi.org/10.1038/nrdp.2017.32 Innate Immunity Deficiencies ▪ Neutropenia Cyclic neutropenia or elastase deficiency Mutation in gene encoding neutrophil elastase, results in decreased enzyme activity – Leads to apoptosis of developing neutrophils Fluctuating counts with periods of infectious risk Frequently presents with severe periodontal disease Nat Genet 35, 90–96 (2003). https://doi.org/10.1038/ng1224 Innate Immunity Deficiencies ▪ Chronic Granulomatous Disease Inability to produce reactive oxygen species in phagocytes Recurrent bacterial infections, often in lungs and skin Defect in NADPH oxidase (Phox) X-linked most common (gp91phox) SOME T and B Cell Immunodeficiencies Common  Subunit of Cytokine Receptors ▪ IL7Rα Critical signaling pathway for the development of T cells and of B cells in mice Some humans have lower antibody levels with IL7Rα deficiency Barata, J.T., Durum, S.K. & Seddon, B. Flip the coin: IL-7 and IL-7R in health and disease. Nat Immunol 20, 1584–1593 (2019) SOME T and B Cell Immunodeficiencies Common  Subunit of Cytokine Receptors ▪ Common  subunit is a component of several cytokine receptors X-linked SCID: Loss of  subunit makes receptors non-functional and signaling is disrupted Critical cytokines for T and B cell maturation and function Fueling Cancer Immunotherapy With Common Gamma Chain Cytokines. Front. Immunol. 10:263. SOME T and B Cell Immunodeficiencies RAG1 and RAG2 Mutations ▪ Recombination Activating Gene Critical enzymes in the process of VDJ recombination in T and B cell development Inactivation mutants leave patients without any T or B cells Hypomorphic mutations – reduced RAG function – Omenn syndrome Allows limited VDJ recombination Susceptible to opportunistic infection Enlargement of lymph nodes Have low level of T cells, no B cells – T cells respond to self tissues (GVHD) DNA-Dependent Protein Kinase ▪ DNA-PK, Artemis, DNA Ligase IV Patients have RS-SCID Radiation sensitive – Lack of repair of DNA breaks from ionizing radiation Also more sensitive to chromosomal breaks during cell division that can cause some cancers Enzymes are all involved in the V(D)J recombination in B and T cells Responsible for ligating DNA breaks Lack of enzyme activity results in failure in both B and T cell maturation Autosomal recessive mutations SOME T and B Cell Immunodeficiencies Purine biosynthetic pathway ▪ ADA and PNP Mutations in either cause a buildup of toxic intermediates B, T, and NK cells are unable to be generated via hematopoiesis DNA synthesis is also impacted – Impacts many cells in the body Progressive lymphopenia occurs after birth Diagnosis and Treatment of SCID ▪ Diagnosis Presents early in life, typically before 4 months of age Frequent infections, often respiratory, by unusual or opportunistic pathogens – Pneumocystis jirovecii – Candida albicans – Herpes viruses Chronic diarrhea Failure to thrive Newborn screening Highly effective for diagnosis T cell receptor excision circles (TREC) screening using dried blood from newborn heel sticks Diagnosis and Treatment of SCID ▪ Treatments Untreated patients typically die by 1 year of age Only treatment is hematopoietic stem cell transplant 90% of patients who receive a stem cell transplant by the age of 3 months survive Bare lymphocyte syndrome, Type 1 MHC Class I Deficiency ▪ Mutations in TAP-1 or TAP-2 No peptides loaded into MHC Class I No activation of CD8 T cells No Cytotoxic T cell response MHC Class I Deficiency ▪ Mutations in TAP-1 or TAP-2 You would predict the patient would be abnormally susceptible to viral infections NOT THE CASE! Suggests alternate mechanism for CD8 T cell control of viruses Patients do have: Bacterial respiratory tract infections, bronchiectasis, skin granulomatous lesions Bare lymphocyte syndrome, Type II MHC Class II Deficiency ▪ Mutation in one of the transcription factors that regulate the expression of Class II MHC genes Do not memorize transcription factor names: CIITA, RFX5, RFXAP, or RFXANK Transcription of Class II MHC genes is inhibited. ▪ Reduced helper T cell maturation due to failed selection in the thymus Reduced antigen presentation to any helper T cells that do mature Decreased humoral and CMI responses ▪ Patients present with severe, recurrent infection Wiskott-Aldrich Syndrome ▪ Genetic defect in WASp (Wiskott-Aldrich Syndrome protein) Expressed by hematopoietic stem cells to stabilize actin cytoskeleton Cells such as platelets and lymphocytes have abnormal sizes, shapes, and functions Ther Adv Rare Dis 2021, Vol. 2: 1–8 Wiskott-Aldrich Syndrome ▪ Genetic defect in WASp (Wiskott-Aldrich Syndrome protein) Red stars: known WASp interaction Blue stars: proposed WASp interaction Front. Immun. 2012. Autoimmunity in Wiskott– Aldrich Syndrome: An Unsolved Enigma Wiskott-Aldrich Syndrome ▪ Clinical presentation: Asthma Eczema Allergic diseases Increased susceptibility to viral infections Herpes Varicella zoster Molluscum contagiosum Increased susceptibility to encapsulated bacterial infections Streptococcus pneumoniae Neisseria meningitidis Haemophilus influenzae Wiskott-Aldrich Syndrome ▪ Treatment Stem cell transplant Success depends on – child's overall health at the time of the procedure – the match between the patient and donor's bone marrow – the child's age at the time of the transplant » Ideally before age of 5 DiGeorge Syndrome ▪ Genetic defect causes underdeveloped thymus Portion of chromosome 22 is deleted Has effects on several body systems – Very low T cell numbers – Some phenotypes are dependent on size of deletion DiGeorge Syndrome ▪ Treatment Thymic transplantation Thymic material taken during elective cardiac surgery has been transplanted without HLA matching or GVHD Non-transplant options Treatment of cardiac abnormalities Prevention of opportunistic infections with antibiotics Long term prognosis Dependent on severity of disease and treatments done Antibody deficiencies Antibody deficiencies ▪ X-linked agammaglobulinemia Recurrent bacterial infections, particularly extracellular Streptococcus pyogenes, Staphylococcus aureus Chronic viral infections Poliovirus, Hepatitis B and C viruses Typically detected months to a year after birth Protection from mother’s IgG wanes before normal Ig production takes off at 6 months Antibody deficiencies ▪ X-linked agammaglobulinemia Mutation in BTK – a kinase important in signal transduction from pre-B cell receptor If a functional pre-B cell receptor is made, signaling occurs for proliferation and differentiation of pre-B cells Btk mutation cannot transmit the signal, apoptosis of pre-B cell Disease is characterized by lack of B cells and lack of serum antibodies Antibody deficiencies ▪ Selective IgA deficiency Many cases are asymptomatic 60-75% do not have clinical manifestations Why? Symptomatic cases are often associated with deficiency in at least one IgG subclass Symptoms are variable – Frequent upper respiratory tract infections by bacterial pathogens – GI infection, often with Giardia – Asthma, eczema, celiac disease, ulcerative colitis Antibody deficiencies Antibody deficiencies ▪ CD40L Hyper IgM syndrome CD40L expressed on activated T cells CD40 expressed on APCs (B cells, dendritic cells, etc) Unable to bind B cells, no class switching Only express IgM Susceptible to extracellular bacteria Also unable to interact with dendritic cells and macrophages Cannot make IL12, which is critical for INFγ production Lower levels of cell mediated immunity Antibody deficiencies ▪ AID deficiency Mutation in activation-induced cytidine deaminase Required for initiation of somatic hypermutation and class switching Produces normal or high concentrations of IgM with low or absent IgG, IgA and IgE Patients have recurrent bacterial respiratory and GI infections Antibody deficiencies Antibody deficiencies ▪ CVID – common variable immunodeficiency Caused by a variety of mutations Defined by having very low serum levels of at least two Ig isotypes IgG plus IgA and/or IgM Lack of antibody response to infection and vaccination Clinician Reviews. 2017 June;27(6):38-42 Antibody deficiencies ▪ CVID – common variable immunodeficiency Diagnosis can occur at any point in life, most often around 2 years or in 20s and 30s Life expectancy varies depending on the severity and frequency of illnesses Caused by a variety of mutations Most cases occur in people with no family history of the disorder and likely result from a complex interaction of environmental and genetic factors – Late onset is due to either low severity of disease or impact of environmental factors – BAFF-R, TACI, CD19, CD21, CD81 are known mutations Antibody deficiencies ▪ Treatment IVIG or SCIG infusions monthly or weekly Pooled donor samples where IgG is purified (IgA and IgM mostly removed) – Pool of between 1,000 to 60,000 donors  Midwestern Wellness Support Professional school can be difficult, we have resources Other Mental Health Resources Student Counselors If you or someone you know are feeling suicidal: Brandy Strom, Psy.D., MS, LPC Krista Sheldon, MSW, LCSW  EMPACT Mobile Crisis Intervention/Suicide Melody McGee-Hillard, MA, Ed.S, LPC, NCC Prevention Center – 24/7 Emergency Mental Health Aaron “Baab” Aster, MA, LPC, NCC Crises, including Suicidal ideation/Suicide 480-736-4952 Please email to request an appointment:  Call or text 988 – 24/7 Confidential Lifeline network crisis center [email protected] Teletherapy (ALL MWU students can access the following free services) Academic Support Academic, Communication, and Language Support Academic Live Care: Amy Woodbeck, M.Ed., M.S.Psy– Learning https://midwestern.myahpcare.com/telehealth to register. 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