Lecture No. 8 Immune Defeciencies PDF

10/27/2022 Lecture No. 8 Immunodeficiency's Chapter 4 Gheyath k. Nasrallah A. Primary Immune Deficiencies 1  10/27/2022 I. Humo...

10/27/2022 Lecture No. 8 Immunodeficiency's Chapter 4 Gheyath k. Nasrallah A. Primary Immune Deficiencies 1  10/27/2022 I. Humoral immune deficiencies a. Bruton or X-linked agammaglobullnemia  gene encoding for Bruton tyrosine kinase (BTK): Western blot analysis coding to nonfunctional protein  Gene important in maturation of pre to mature B cells  Rare: 1:200,000 female  B cells are markedly decreased or absent (CD19/20).  A marked deficiency of all classes of immunoglobulins  is detected after about 6 months of age.  Recurrent, life-threatening infections occur with encapsulated bacteria, such as Streptococcus pneumoniae and Haemophilus infiuenzae, manifested as pneumonia, sinusitis, bronchitis, otitis, furunculosis (deep folliculitis), meningitis, and septicemia. mainly upper respiratory disease I. Humoral immune deficiencies b. Hyper-IgM syndrome (HIGM) the costimulatory molecule for switching from b cells to plasma  5 types: different genes involved mainly CD40  X-linked genetic disease: a defect in CD40 ligand (signaling) on T helper cells prevents class switching from IgM to IgG, lgA, or lgE.  Serum IgM is increased; IgG and lgA are markedly decreased or absent.depends on the mutations some mutations are completley defective while some are non functional  Affected individuals are prone to respiratory tract infections (pneumonia).  Affected individuals often have autoantibodies to platelets, red blood cells, and neutrophils IgM can bind nonspecifically to these 2  10/27/2022 I. Humoral immune deficiencies mainly impacted by mucosal infections c. Selective IgA deficiency (SIgAD)  Patients present with small amounts or absence of serum and secretory IgA and normal IgG  Similar to common variable immunodeficiency (CVID).  Usually caused by a genetic defect or by drugs [phenytoin (anti-seizure medication) and penicillin]  Anaphylaxis due to blood transfusion: may result if IgA is administered to someone with this deficiency  85–90% of IgA-deficient individuals are asymptomatic.  Pneumonia is common between symptomatic patients we will check the gene expression in diff types of tissue identify where is it expressed highly or not expressed in the tissue I. Humoral immune deficiencies d. Ataxia-telangiectasia  Ataxia: is a neurological sign consisting of lack of voluntary coordination of muscle movements  Telangiectasia: is a condition in which widened venules (tiny blood vessels) cause threadlike red lines or patterns on the skin.  Appear during childhood (walking age)  It is not primarily an immunodeficiency but a defect in a kinase telangiectasia gene that regulates the cell cycle.  Autosomal recessive disorder that presents with ataxia, telangiectasia, recurrent sinopulmnonary infections, a high incidence of malignancy (defective DNA repair mechanism), and variable immune defects. spider veins  Patients typically present with an lgA and sometimes IgE deficiency.  The B and T helper cells are affected. 3  10/27/2022 2. Cellular immune deficiencies happens in metabolic genes or mhc 1 or 2 expression genes  Mixed: Because T cells are involved in both humoral- and cell-mediated responses, individuals with T helper cell deficiencies can have a severe combined immunodeficiency. Congenital thymic hypoplasia (DiGeorge syndrome)  Caused by: aplasia or underdevelopment of the thymus and parathyroid gland (pharyngeal pouch).the thymus and parathyroid originate both types of stem cells  Symptoms include:  hypocalcemic tetany (muscle spasm): low extracellular calcium leads to influx of increase permeability of neuronal cells to sodium ions: membrane depolarization  Heart disease.  Immune defect is variable, from slight decrease in T cell to no T cells in the bloodstream, decreased CD4/CD8+ ration.  Patients are very susceptible to opportunistic infections and have a poor prognosis  Some patient dies at age of 1 year because of sepsis the development of disease- higher chance to die 3. Severe combined immune deficiency  group of diseases: with different causes, that affect T and B cell  function, resulting in a suppression of HMI and CMI responses cytosine and guanine problem in cells that are always replicating such as wbcs  Example1: Defects in adenosine deaminase (ADA) or purine nucleotide phosphorylase (PNP)  Absence of these enzymes causes an accumulation of nucleotide metabolites in all cells, which is particularly toxic to T and B cells.  Very low number of T cells is present  Children often have an underdeveloped thymus, lack of tonsils or lymph nodes, hypogammaglobulinemia, and lymphopenia. 4  10/27/2022 3. Severe combined immune deficiency Example 2: Bare lymphocyte syndrome  With an MHC class II deficiency: T helper cells fail to develop.  Patients present with hypogamaglobulinernia and no CMI response.  MHC class I deficiency is less severe: There is a loss of CTLs and response to intracellular pathogens. Example3: Wiskott-Aldrich syndrome  Mutation in the gene that codes for the Wiskott-Aldrich syndrome protein (WASP)  WASP involved with cytoskeletal reorganization necessary for delivering cytokines steramonocytogenes recruits the  The defect prevents T helper cells from delivering lymphokines to B cells, macrophages, and other target cells.  Patients demonstrate eczema, thrombocytopenic purpura, and increased risk of infection.  Platelets are small and defective. 4. Complement deficiencies a. Genetic deficiencies have been described for each of the complement proteins. b. Homozygous deficiencies in any of the early components of the classical complement proteins result in an increase in immunecomplex diseases. c. Patients with defects in early alternative complement proteins, such as factor D and properdin, are susceptible to infections by Neisseria meningitidis. d. Patients with a C3 defect have the most severe clinical manifestations. e. Check: Properdin Deficiency, Hereditary Angioedema (HAE), Familial Mediterranean Fever (FMF) 5  10/27/2022 B. Secondary Immune Deficiencies B. Secondary Immune Deficiencies 1. Secondary immune deficiencies are due to an underlying cause. 2. Transient hypogammaglobulinemia of infancy presents as a decline in serum immunoglobulins during the first few months of life. Individuals eventually produce normal amounts of immunoglobulins. 3. Malignancy a. Cancers can exert a suppressive effect on the immune system. b. Impairment of antibody production is found in lymphomas, chronic lymphocytic leukemia, and multiple myeloma. 4. Viral disease: Certain viruses impair the function of the immune system such as HIV, EBV, CMV 5. Nutritional deficiencies and defects: Malnutrition and protein-energy malnutrition syndromes (e.g., marasmus) 6  10/27/2022 Serum electrophoresis Albumin. Albumin proteins keep the blood from leaking out of blood vessels. Albumin also helps carry some medicines and other substances through the blood and is important for tissue growth and healing. More than half of the protein in blood serum is albumin. Alpha-1 globulin. High-density lipoprotein (HDL), the "good" type of cholesterol, is included in this fraction. Alpha-2 globulin. A protein called haptoglobin, which binds with hemoglobin, is included in the alpha-2 globulin fraction. Beta globulin. Beta globulin proteins help carry substances, such as iron, through the bloodstream and help fight infection. Gamma globulin. These proteins are also called antibodies. They help prevent and fight https://www.uofmhealth.org/health-library/hw43650 infection. Gamma globulins bind to foreign substances, such as bacteria or viruses, causing them to be destroyed by the immune system. B. Secondary Immune Deficiencies (hypergammaglobulinemia) A. Polyclonal Hypergammaglobulinemia : Tremendous amounts of several classes of immnunoglobulins to several specific antigens are produced, resulting in a broad spike in the gamma region on serum protein electrophoresis. 1. Infectious diseases: Chronic antigenic stimulation from infectious organisms can create this condition. 2. Inflammatory process: Many acute-phase proteins are produced during inflammation and can cause a broadening of the alpha-2 peak in serum protein electrophoresis. 3. Liver disease: Because of a polyclonal increase in the gamma region and an increase in IgA, the depression between the gamma and the beta regions is absent. As a result, the beta and gamma regions form only one peak on serum protein electrophoresis-beta-gamma bridging, consistent with cirrhosis 7  10/27/2022 B. Secondary Immune Deficiencies (hypergammaglobulinemia) B. Monoclonal Hypergammaglobulinemia: is a malignant transformation of a clone of B cells that produce identical antibodies. This causes a narrow peak on serum protein electrophoresis. 2. Multiple myeloma a. Lymphoproliferative disease: plasma cells produce a high concentration of different classes of Ig b. Approximately 50% of patients with multiple myeloma have Bence Jones protein (light chain fragment) in their urine. Mainly IgG followed by IgA and then IgM. c. Symptoms: Weakness, anorexia, weight loss, skeletal destruction, pain, anemia, renal insufficiency, and recurrent bacterial infections d. Laboratory findings: Monoclonal gammopathy and plasma cell infiltrate in bone marrow e. Monoclonal immunoglobulins (M-proteins) I) Diagnostic of multiple myeloma, Waldenstrorn macroglobulinemia, chronic lymphocytic leukemia, or lymphoma 2) Immunoglobulin type determination is necessary for diagnosis & prognosis. B. Secondary Immune Deficiencies (hypergammaglobulinemia) Waldenstrorn macroglobulinemia Monoclonal immunoglobulins (M-proteins) a. Cause unknown: Uncontrolled proliferation of a clone of B cells that synthesize a homogeneous IgM b. Hyperviscoslty of plasma: causes congestive heart failure, headache, dizziness, partial or total loss of vision, bleeding, and anemia. c. Symptoms: Weakness, fatigue, headache, and weight loss d. Laboratory findings: A spike in the beta or gamma region on serum protein electrophoresis, increased plasma viscosity, and abnormal accumulation of lymphoid cells in the bone marrow and tissues 8  10/27/2022 B. Secondary Immune Deficiencies (hypergammaglobulinemia) 4. Primary amyloidosis  normal biological functions! amyloid protein for example, in the formation of fimbriae in some genera of bacteria, transmission of epigenetic traits in fungi, as well as pigment deposition and hormone release in humans.  An amyloid protein is a nonstructural protein that becomes insoluble after an alteration in its secondary structure.  These proteins accumulate in organs and tissue.  Monoclonal plasma cell disorder: abnormal immunoglobulin or Bence Jones protein, or less commonly, heavy chain fragment is produced.  Insoluble proteins are deposited in some of the tissues: skin, liver, nerves (Alzheimer, prions), heart, kidney, etc. This results in progressive loss of organ function.  Laboratory findings: frequent abnormalities of serum immunoglobulins and presence of Bence Jones proteins 9