Lecture 16.pdf

The Primary Immunodeficiencies Dr David van Bockel | 25.03.2024 Kirby Institute for Infection and Immunity [email protected] 1 Learning outcomes From this lecture you are expected to understand: The definition and classification of primary immunodeficiencies Primary immunodeficiencies by...

The Primary Immunodeficiencies Dr David van Bockel | 25.03.2024 Kirby Institute for Infection and Immunity [email protected] 1 Learning outcomes From this lecture you are expected to understand: The definition and classification of primary immunodeficiencies Primary immunodeficiencies by example and their source expressed in biological or genetic terms Infections that result from primary immunodeficiencies and the reasons Typical and prospective treatments 2 Primary Immunodeficiencies Primary immunodeficiencies are groups of genetic disorders, resulting in defects in immune system development and function. Important clinical problems (but rare) Inability to control infections, which can lead to a limited lifespan Possible increase in cancers and autoimmune diseases Genetic defects for many of these problems now understood (whole genome / exome sequencing) Number of syndromes linked to specific gene defects continuously increasing 3 Primary Immunodeficiencies Cells: Innate Phagocytes Neutrophils Monocytes/macrophages Dendritic cells Adaptive (Lymphocytes): CD4 (T-cell help) CD8 T cells (cytotoxic T-lymphocytes) B cells (antibodies) Proteins: Complement Toll Like receptors cytokines 4 Primary Immunodeficiencies Complement 2% Phagocytic defects 18% Antibody 50% T Cell and Combined 30% http://www.jmfworld.com/1996_WHO.pdf 5 Primary Immunodeficiencies (PID) Rare (~1/10,000 births) >400 syndromes or diseases described that relate to PID#, some extremely rare Predominantly inherited, so are also referred to as ‘Inborn Errors in Immunity’ (IEI), some sporadic Due to mutations in genes which affect the immune response ( >320 have genes/mutations discovered) Mutations in immune response genes tell us a lot about the normal function of that gene (these can be thought of as “experiments in nature”) #Australasian Society of Clinical Immunology and Allergy (https://www.allergy.org.au/patients/immunodeficiencies) 6 Primary Immunodeficiencies: summary Primary Immunodeficiencies: summary B-cell defects Result in defective or complete lack antibody production = infection What? Recurrent bacterial infections Especially encapsulated/pyogenic (pus forming) organisms H. influenzae, Staph. aureus, Strep. pneumonia, Pseudomonas Where? Upper and lower respiratory tracts Middle ear infections Sinus Pneumonia Bronchitis Gastrointenstinal (chronic diaorrhea) When? If severe or complete block, from 4-12 months of age as maternal immunity wanes Males more than females (most are X linked), when recessive females can also be affected Who? 9 B-cell defects B-cell maturation: 10 B-cell defects Example: X-linked agammaglobulinaemia X-linked hypo-(a)gammaglobulinaemia (XLA; 1 in 250,000 population) Is a condition in which a person has very low levels of serum immunoglobulin High level of hereditary passage (~40% family association) Loss of all B cells and all antibody classes Bruton's tyrosine kinase (Btk) mutation leads to a loss of the BTK (tyrosine kinase) protein which is essential for B-cell development. The block is at the pre-B cell to immature B cell stage Treatment: Replacement Immunoglobulin given as monthly infusions. Receiving treatment these individuals can live near normal lives. 11 B-cell defects X-linked agammaglobulinaemia: 12 B-cell defects Example: Selective IgA deficiency (IGAD) 1 in 700 Caucasians No IgA (some still have IgA, but very low level) Some patients also have a low level of IgG The mechanism is currently unknown B cells from patients have the capacity to secrete IgA, but are unable (in vivo) Many have no disease Increase in chronic lung disease, autoimmunity and allergic disease (IgA protects against infections of the mucous membranes lining the mouth, airways, and digestive tract, half-life of 6 days) IGAD associations Auto-immune disorders: systemic lupus erythematosus, Rh arthritis, ITP Mutations in HLA-DR genes Currently, no specific treatment 13 B-cell defects Example: Common variable immunodeficiency (CVID) Incidence 1:25,000-50,000 worldwide Prevalence in males equal to females, late-onset of symptoms often in teens, twenties (late-onset hypogammaglobluinemia) Cause: 90% cases are currently unknown. 10% related to genetic cause (cluster of at least 13 variants) = risk factor to disease susceptibility, i.e. not causative Mutations occur in: ICOS (Inducible T-cell Co-stimulator), CD19 (B-lymphocyte antigen), BAFF-R (TNFRSF13C, B-cell survival receptor), TNFRSF13B (TACI; cell signalling protein) gene sets. The TNF receptor superfamily member 13B is expressed on the surface of B cells and effects their ability to mature, survive and production of antibody. Syndrome: Defective antibody production and ability to respond to vaccination Decreased IgG, IgA and IgE. The level of IgM may be low, normal or higher. Probably mix of several defects Recurrent Infections: Respiratory: Gut: Cancer: Treatment: chronic otitis, chronic sinusitis, bronchitis and pneumonia enterovirus, giardia, Campylobacter jejuni, food absorption lymphoreticular (collective system: spleen, nodes, thymus and nodes) and gastrointestinal tract IgG replacement, survival 58% 45 years after the diagnosis 14 Primary Immunodeficiencies: summary T-cell defects (isolated) What: Absent or defective T cell function Multiple genetic defects (very rare) Where: Manifestations Viral Intracellular pathogens Disseminated fungal infection Opportunistic infections When: Infancy Who: Males and females Treatment: Bone marrow transplant 16 T-cell defects (isolated) Example: Chronic mucocutaneous candidiasis Cause: Hereditary defect in the IL-17 pathway Mutation in the signal transducer and activator of transcription 1 gene (STAT1) IL-17 and IL-22 are important for protection Candida albicans at mucosal surfaces. Syndrome: Chronic infections with Candida albicans (common yeast infection) Limited to mucosal surfaces, skin and nails Associated with other types of infections (i.e. human papilloma virus infection) Mean age of onset 3 years old. Life span is not affected. 17 Primary Immunodeficiencies: summary Combined T- and B-cell defect Example: SCID (severe combined Immunodeficiency syndrome) Combined T and B cell defect: 1 in 58,000 livebirths (70 each year in USA). Defects in Cell Mediated immunity (CMI) and antibody production Many forms of SCID (due to defects in different genes that affect the immune system) Multiple (>12) genes are linked and the most common autosomal recessive SCID results from adenosine deaminase (ADA) deficiency which is critical for T-cell survival. Manifestations: Life threatening infections in infants (ear, lung, thrush, chronic diarrhea) Healthy at first but fatal within 2 years of life Low virulence organisms that usually don’t normally cause severe or extensive disease: Pneumocystis carinii Yeast: Candida sp. Viruses: Cytomegalovirus (CMV) Intracellular pathogens: Mycobacterium Usually, T cells and NK cells are absent, the numbers of B cells and other cells may be low, normal or higher however B-cells characteristically do not function. 19 Combined T- and B-cell defect (SCID) Example: X-linked severe combined immunodeficiency (X-SCID) Defects in common gamma chain (ɣc) of cytokine receptors for cytokines*: IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 None of these cytokines can work, no receptor to bind Multiplication of defect from one cytokine Most common form Hereditary, >90% passed down from maternal X-chromosome Example: Omenn Syndrome Defects in genes that allow rearrangement of T cell receptor and B cell receptor (recombination activating genes (Rag)1 and 2 defects Rag-1 and Rag-2 are involved in V(D)J recombination of TCR and BCR Without VDJ recombination, T cells and B cells lack the diversity of TCR and/or Immunoglobulins to recognize and fight invading pathogens. Whilst T cells and B cells are produced, they are not functional and limited in number. *Dwyer_Frontiers in Immunology_2019 (doi.org/10.3389/fimmu.2019.00263) 20 Combined T- and B-cell defect (SCID) When: Infancy Who: Males more than females (“boy in the bubble”) Treatment: Hematopoietic stem-cell transplant from closely related sibling (pref. at Many cured of SCID but then succumbed to cancer, as the gamma retrovirus inserted gene at and around proto-oncogenes. -> Gene therapies are now turning to lentiviral based vectors based on HIV-1 based proteins. Given HIV can enter resting immune cells and does not preferentially integrate genes in and around proto-oncogenes, this is seen as a step forward in addressing gene deficiencies with a safe clinical outcome. 22 Combined T- and B-cell defect (SCID) 23 Combined T- and B-cell defect (SCID) The story of Max Agit (NIAID): https://youtu.be/yLqhEZKxsoo Courtesy: National Institute of Allergy and Infectious Diseases 22 Combined T- and B-cell defect Example: X-linked Ig deficiency with Hyper-IgM (Hyper IgM syndrome) X-linked defect is responsible for 70% of IgM syndromes Intact IgM response (normal to high IgM) Cannot produce IgG, IgA or IgE IgM can be produced by B cells without T cell help, but isotype switching requires CD4 T cell help. No germinal centres in lymph nodes Lack CD40 ligand (Xq26) CD40L expressed of activated T cells to provide help to B cells. 24 Combined T- and B-cell defect CD40/CD40L dependence of isotype switching 25 Combined T- and B-cell defect CD40/CD40L dependence of isotype switching 26 Primary Immunodeficiencies: summary Innate immune defect Phagocytes Example: Chronic Granulomatous disease (1 in 200,000 live births) Normal phagocytosis but defect in production of toxic oxygen species that kill and degrade engulfed organisms Who: – 1 in 106 in USA: 66% X-linked therefore male (infant onset) Manifestations: – Infections recurrent bacterial infections in children especially with pyogenic bacteria skin, upper and lower respiratory tract and GIT Treatment: – IFN-γ will increase production of reactive oxygen species – Bone marrow transplant 28 Innate immune defect Example: Aicardi- Goutières syndrome (AGS) Chronic inflammation that resembles a chronic viral infection Mutations in the SAMHD1 protein Early onset in children resembles a congenital viral infection Essentially innate immune signaling virus in the absence of infection 29 Any questions?