Midterm-Week-4-Immunodeficiencies PDF

Immunodeficiency Disorders Chap 19, Stevens  Objectives Understand the concept behind immunodeficiency disorders Classify immunodeficiency disorders based on cause and components involved Identify the different mechanisms of each immunodeficiency disorder ...

Immunodeficiency Disorders Chap 19, Stevens  Objectives Understand the concept behind immunodeficiency disorders Classify immunodeficiency disorders based on cause and components involved Identify the different mechanisms of each immunodeficiency disorder  Introduction Definition Immunodeficiency is when the immune system errs by failing to protect the host from disease- causing agents or from malignant cells. Classification 1. Based on the cause 2. Based on component affected  Classification 1. Based on Cause – Primary Immunodeficiency conditions resulting from a genetic or developmental defect in the immune system 6 months of age – Secondary Immunodeficiency loss of immune function and results from exposure to various agents Infection, treatment, cancer, malnutrition Anytime of life  Classification 2. Based on Component Affected – Complement Lack of MAC/Cytolysis → intracellular bacteria → recurrent infections (Neisserial infections) – Phagocyte Pyogenic infections (i.e. caused by bacteria) No cell to engulf and eliminate these low virulent bacteria – B cell without antibody production, no IgG to opsonize Encapsulated bacteria (S. pneumoniae) – T cell RECURRENT VIRAL, FUNGAL, AIDS (affects CD4 Thelper cells) & PROTOZOAL INFECTIONS  Types of Immunodeficiencies (Component Affected) B Cell T cell Combined B & T Phagocyte C’ Bruton's X-linked DiGeorge Severe Combined Chronic MAC Aggamaglobulinemia Syndrome Immunodeficiency Granulomatous Deficiency Disease Common Variable Purine - a. Bare Lymphocyte Chediak- C CHON Immunodeficiency nucleoside Syndrome Higashi deficiency Disorders phosphorylase b. X-linked SCID Syndrome deficiency c. Adenosine Deaminase Transient Deficiency Leukocyte Hypogammaglobulinemia Adhesion of the Newborn Defect Hyper IgM Hyper IgE Wiskot-Aldrich Syndrome IgA deficiency Ataxia Telangiectasia Isolated IgG Subclass Deficiency B CELL SYSTEM DEFICIENCIES AGAMMAGLOBULINEMIA Inherited disorder → low levels of protective immune system proteins (immunoglobulins) → more likely to get infections. Review: B Cell Ontogeny Tyrosine kinase – enzyme needed for differentiation into a mature B cell  B Cell Immunodeficiencies 1. Bruton’s X-Linked Agammaglobulinemia – Is a rare genetic disorder that affects the body's ability to fight infection X linked- males are more affected females are carriers – 1952 – Dr. Ogden Bruton – Absence of BTK gene (encodes for BTK nz) – Immature B cells will not mature – Symptoms appear after 6-9 months of age – lack of B cells, the tonsils and adenoids are small or entirely absent, lymph nodes lack germinal centers.  B Cell Immunodeficiencies 2. Common Variable Immunodeficiency (CVI) – Failure of mature B cells to become plasma cells – No Antibody production – Presentation → IgA and IgG deficiency – Unknown mechanism (idiopathic) 10% of cases have genetic mutation Occurs → children and adolescents B – (+) B cell: CD19 and CD20 Nylon test T Electron microscopy Mitogen (LPS, Dextran, Pokeweed seed)  B Cell Immunodeficiencies 3. Transient Hypogammaglobulinemia – Failure of B cells to produce antibodies (delayed synthesis of Abs) → idiopathic or may be due to delayed maturation of one or more components of the immune system (Th cells) – Also referred to as Pediatric Hypogammaglobulinemia – Starts after 6 months or upon clearance of maternal IgG, there is persistently lower IgG levels that can persist for a longer time…last up to 3 years  REVIEW IgM → IgG Class Switching B cell Th1 CD40 CD40 ligand CD40 present on the surface of B cells will react with CD40 ligand on Thelper cells to initiate class switching of IgM to IgG  B Cell Immunodeficiencies 4. X-Linked Hyper IgM Syndrome – mutations in a gene on the X chromosome that encodes a protein (CD154, or CD40 ligand) on the surfaces of activated helper T cells. – Increased levels of IgM – Low levels of all other isotypes: IgG, IgA, IgD, IgE – Absence of CD40 ligand on Thelper cell – No class switching  Review: Antigen Presentation ATOPIC INDIVIDUALS = produce abnormally elevated amounts of IgE in their blood = susceptible to allergic rxn  B Cell Immunodeficiencies 5. Hyper IgE – Impaired IL-2 production – Hyperactive Th2 – More IgEs in the blood stream than any other isotype – Prone to allergic reactions IL-2 M Th1 B cell PC IL-4 IL-13 PC M Th2 B cell  B Cell Immunodeficiencies 6. IgA deficiency – Most common primary immunodeficiency – Unknown mechanism (idiopathic) – Failure of B cells to become IgA- producing plasma cells – Prone to infections of the mucous membranes lining the mouth, airways, digestive tract. Recurrent gastrointestinal and respiratory infection  B Cell Immunodeficiencies 7. Isolated IgG Subclass Deficiency – person lacking a specific IgG subclass → vulnerable to certain kinds of infections but not others – Protein antigens: IgG1 and IgG3 serious bacterial infections (diphtheria and tetanus), & viruses – Carbohydrate antigens: IgG2 Deficiency can lead to impaired protection against antigens like encapsulated bacteria (S. pneumoniae, H. influenzae) IgG Subclass Concentration in the Blood IgG1 IgG2 IgG3 IgG4 70% 20% 6% 4% T CELL SYSTEM DEFICIENCIES CELLULAR IMMUNITY DEFICIENCY  T Cell Immunodeficiency 1. DiGeorge Syndrome / DiGeorge Anomaly – 22q11.2 Deletion Syndrome (location) – Absence of chromosome 22q – Impaired development of 3rd and 4th pharyngeal pouch that gives rise to: Hard palate Part of aorta Parathyroid gland Thymus DiGeorge Syndrome / Anomaly CATCH 22 Cleft palate Abnormal faceii Thymic hypoplasia Cardiovascular disorder Hypocalcemia  T Cell Immunodeficiency 2. Purine-nucleoside phosphorylase deficiency – PNP nz → housekeeping nz → clears waste molecules that are generated when DNA is broken down. When DNA is broken down, production of purines – mutations in the PNP gene → eliminate the activity of purine nucleoside phosphorylase – Accumulation of deoxyguanosine triphosphate (waste molecules) → toxic to immature T lymphocytes in the thymus Number of T cells progressively decreases – S/S: Neurologic disorders Recurrent or chronic pulmonary infections, diarrhea, urinary tract infections (UTI), skin infections Combined Deficiencies of Humoral and Cellular Immunity COMBINED B & T CELL DEFICIENCIES  Combined B Cell & T Cell Immunodeficiencies 1. Severe Combined Immunodeficiency (SCID) – 3 SCID Types: a. Bare Lymphocyte Syndrome / TAP-2 deficiency– mutations in https://www.youtube.c genes coding for MHC → absence of om/watch?v=pJa6KV Type I (MHC Class I) Type II (MHC Lwl9U&t=10s Class II) → no loading of peptide fragments Nucleated APCs cell Th  Combined B Cell & T Cell Immunodeficiencies – SCID Types: b. X-Linked SCID – absence of receptors for IL-7 and IL-15 IL-3 IL-7 & IL-15 IL-7r & IL-15r  Combined B Cell & T Cell Immunodeficiencies – SCID Types: c. Adenosine Deaminase Deficiency – mutations in the ADA gene that codes for adenosine deaminase enzyme Immature lymphocytes in the thymus are vulnerable to a toxic buildup of deoxyadenosine → die before they can mature → severe reduction in the number of lymphocytes → The loss of infection-fighting cells results in the signs and symptoms of SCID.  Combined B Cell & T Cell Immunodeficiencies 2. Wiskott-Aldrich Syndrome (WAS) – abnormality in integral membrane (CD43); Gene responsible for defect: WASp gene (Wiskott-Aldrich Syndrome protein) Decreased platelet survive Abnormal skin function Triad of WAS Defects in T and B cell function  Combined B Cell & T Cell Immunodeficiencies 3. Ataxia-Telangiectasia (AT) Syndrome – aka Louis- Bar syndrome is a neurodegenerative inherited disorder ; absence of ATS gene which codes for ATM protein Ataxia refers to poor coordination and telangiectasia to small dilated blood vessels (hallmark) Synthesized proteins: T cell receptors Ig isotypes Defects of Neutrophil Function PHAGOCYTE IMMUNODEFICIENCIES  Phagocyte Immunodeficiencies 1. Chronic Granulomatous Disease (CGD) – absence of NADPH oxidase ; suppurative infections * Core defect: failure of phagocytes to kill engulfed organisms due to defects in a system of enzymes that produce free radicals and other toxic small molecules.  Phagocyte Immunodeficiencies 2. Chediak-Higashi Syndrome – absence of LYST gene (lysosomal trafficking) which codes for LYST protein, important in the fusion of lysosome with phagosome) * ALBINISM: transport of melanin to melanocytes fails  Phagocyte Immunodeficiencies 3. Leukocyte Adhesion Defect / Deficiency * Lazy Leukocyte Syndrome – Type I: absence of integrin – Type II: absence of L-selectin (CD62L) → cell adhesion molecule found on lymphocytes Sialyl-Lewis X-modified glycoprotein (CD15s) Capture / Margination Diapedesis  Continuation… 3. Leukocyte Adhesion Defect / Deficiency – Also absence of CD18/CD11 adhesion receptors on T cells, neutrophils, and monocytes – Results in abnormal adhesion, motility, and chemotaxis of cells – S/S: Delayed wound healing Chronic skin infections  Complement Component Deficiency Lack of MAC (C5b6789) No cytolysis of (intracellular) pathogen Recurrent infection