Immunodeficiency Disorders PDF

◤ Immunodeficiency Disorders Lecture: Dr Rozhan Nabaz M MBChB CABP ◤ Learning objectives By the end of this session student should be able to recognize: ▪ Genetic, pathogenesis and clinical presentation of some common types of Primary immunodeficiency ▪ Secondary immunodeficiency diseases....

◤ Immunodeficiency Disorders Lecture: Dr Rozhan Nabaz M MBChB CABP ◤ Learning objectives By the end of this session student should be able to recognize: ▪ Genetic, pathogenesis and clinical presentation of some common types of Primary immunodeficiency ▪ Secondary immunodeficiency diseases. Immune System Module ◤ DEFINITION AND CLASSIFICATION ▪ Immunodeficiency - state where the defence mechanisms of the body are impaired, leading to enhanced susceptibility to microbial infections as well as to certain forms of cancer. ▪ Immunodeficiency diseases are broadly classified as: o Primary immunodeficiency Immune System Module o Secondary immunodeficiency ◤ PRIMARY IMMUNODEFICIENCY DISEASES Immune System Module Humoral immunodeficiency (B cell defects) 1 Bruton disease (X-linked agammaglobulinemia) 2 Common variable immunodeficiency 3 Isolated IgA deficiency 4 Hyper-IgM syndrome 5 Transient hypogammaglobulinemia of infancy Cellular immunodeficiencies (T cell defects) 1 DiGeorge syndrome (Thymic hypoplasia) 2 Chronic mucocutaneous candidiasis 3 Purine nucleoside phosphorylase (PNP) deficiency Combined immunodeficiencies (B and T cell defects) 1 Severe combined immunodeficiencies ∙ Cytokine receptor mutation ∙ Adenosine deaminase (ADA) deficiency 2 Wiskott-Aldrich syndrome 3 Ataxia telangiectasia 4 Nezelof syndrome ◤ PRIMARY IMMUNODEFICIENCY DISEASES Disorders of phagocytosis 1 Chronic granulomatous disease 2 Myeloperoxidase deficiency 3 Chediak-Higashi syndrome 4 Leukocyte adhesion deficiency 5 Lazy leukocyte syndrome 6 Job's syndrome or Hyper-IgE syndrome 7 Tuftsin deficiency 8 Shwachman's disease Disorders of complement* Immune System Module 1 Complement component deficiencies 2 Complement regulatory protein deficiencies Immune System Module ◤ Infections in Immunodeficiencies Immune System Module Pathogen T-Cell Defect Type B-Cell Defect Granulocyte Defect Complement Defect Bacteria Bacterial sepsis Streptococci, Staphylococci, Staphylococci, Pseudomonas Haemophilus Nocardia influenzae Neisseria, Other pyogenic infections Viruses Cytomegalovirus, Epstein-Barr virus, Severe varicella, Chronic infections with respiratory and intestinal viruses Enterovirus encephalitis - ◤ Infections in Immunodeficiencies Pathogen T-Cell Defect B-Cell Defect Type Fungi Candida, Pneumocystis jirovecii Parasites Special Aggressive disease features with opportunistic pathogens, failure to clear infections Immune System Module Giardiasis Recurrent sinopulmonary infections, Sepsis, chronic meningitis Granulocyte Defect Candida, Aspergillus - Complement Defect Neisseria, Other pyogenic infections ◤ Bruton disease (X-linked agammaglobulinemia) ▪ Failure of pre-B cells to differentiate into immature B cells in the bone marrow. Naïve B cell ▪ Due to absence of an enzyme called Bruton’s tyrosine kinase (transformation of pre-B cell into immature B cell) 🡪 Total absence of B cells and plasma cells in the circulation. BTK Plasma cells ▪ Pre-B cells are found in normal numbers in bone marrow and the T-cell-mediated responses are also normal. Immune System Module ▪ Cytoplasm of pre B cell may have incomplete immunoglobulins. IgG IgM IgA IgE ◤ ▪ X linked, primarily in males; nevertheless, sporadic cases have been described in females. ▪ Secondary infections are seen after 6 months of age, when maternal antibodies are depleted. o Recurrent bacterial infections (e.g., Haemophilus influenzae, Streptococcus pneumoniae, or Staphylococcus aureus) leading to acute and chronic pharyngitis, sinusitis, otitis media, bronchitis, and pneumonia. o Viruses that are cleared by neutralizing antibodies- e.g. enteroviruses o Parasites which are usually resisted by secretory IgA- e.g. Giardia lamblia. Immune System Module ▪ Autoimmune diseases (such as SLE and dermatomyositis) also occur in up to 20% of cases. ▪ Avoid live vaccines ▪ Diagnosis: flow cytometry, no antibodies ◤ Common Variable Immunodeficiency ▪ Heterogeneous group of both sporadic and inherited forms of the disease. ▪ Hypogammaglobulinemia, increased susceptibility to infection, autoimmune disorders (hemolytic anemia, pernicious anemia), as well as lymphoid tumors. Immune System Module ◤ ▪ The clinical manifestations are superficially similar to those of Bruton diseases; but differ in the following aspects: Immune System Module o Both sexes are affected equally o Onset of symptoms is much later, in the second or third decade of life. o Diagnosis is usually one of exclusion (after other causes of immunodeficiency are ruled out); the basis of the immunoglobulin deficiency is variable (hence the name). o Intrinsic B-cell defects, deficient T-cell help, or excessive T-cell suppressor activity. ◤ Isolated IgA deficiency ▪ Most common, affects about 1 in 700 white individuals. ▪ Weakened mucosal defences due to IgA deficiency predispose patients to recurrent sinopulmonary infections and diarrhea. ▪ Significant (but unexplained) association with autoimmune diseases. ▪ Allergic disorders Immune System Module ▪ Anaphylactic transfusion reactions Increased risk of anaphylaxis to IgA containing materials: blood, plasma, or IVIG ◤ ▪ Pathogenesis: o Block in the terminal differentiation of IgA-secreting B cells to plasma cells (due to altered T-cell production of cytokines or intrinsic B-cell defect). o The levels of other immunoglobulins are usually normal or even excess. Immune System Module ◤ Hyper-IgM syndrome ▪ X-linked disorder - due to a defect in isotype class switch over of B cells. ▪ Class switch over depends upon two signals generated by helper T cells which influence the B cellso TH cell induced cytokine o Signal generated due to direct contact through Immune System Module the interaction of CD40 molecules on B cells with CD40 ligand (CD40L) on TH cells. ◤ ▪ Mutations in either CD40L or CD40 genes; prevent the T- and B-cell interaction – blocks the class switch over 🡪 lack of synthesis of other classes of antibodies. ▪ Deficiency of IgG - defect in opsonization and complement activation (predisposes to recurrent pyogenic infections) and IgA deficiency leads to increased recurrent sinopulmonary infections and diarrhea. Immune System Module ◤ ▪ Excess IgM antibodies 🡪 autoimmune hemolytic anemia, thrombocytopenia, or neutropenia. ▪ Patients with defect in CD40L are more susceptible to Pneumocystis jirovecii infection. ▪ X linked- Hyper-IgM syndrome is X-linked in 70% of the cases affecting males; in the remaining patients, the precise mutations have not been fully characterized. Immune System Module ◤ DiGeorge syndrome (thymic aplasia) ▪ Results from a congenital defect in thymic development leading to defect in T-cell maturation. ▪ Infants are extremely vulnerable to viral, fungal, intracellular bacterial and protozoan infections. ▪ Pathogenesis- In 90% of cases, there occurs a deletion affecting chromosome 22q11 which leads to developmental malformation affecting the third and fourth pharyngeal pouches in embryonic life. ▪ Thymus, parathyroid glands, and portions of the face and aortic Immune System Module arch become defective. ◤ ▪ There may be associated: o Parathyroid resulting in hypocalcemia gland neonatal hypoplasia tetany and o Anomalies of the heart and the great vessels (Fallot's Tetralogy). o Characteristic facial appearance ▪ Treatment- Thymus transplantation has Immune System Module been found to be successful in restoration of immune function. In others (with partial defects), immunity may improve spontaneously with age. ◤ Severe combined immunodeficiencies (SCID) ▪ Represents groups of genetically distinct syndromes; all having in common, defects in both humoral and cell-mediated immune responses. ▪ Types of genetic defect in SCID include: o Mutation in cytokine receptor - Approximately 50-60% of the cases of SCID are X-linked (seen in males). -The IL2RG gene encodes the γc portion and mutations in the IL2RG gene can cause X-SCID. Immune System Module -Not only does the common γc portion interact with the IL-2 cytokine, but it is also shared by other leukocyte cytokine receptors (IL-4, IL-7, IL-9, IL-15, and IL-21). ◤ o Adenosine deaminase (ADA) deficiency – is AR and second most common SCID, after X-linked SCID (IL2RG), ADA deficiency leads to accumulation of deoxyadenosine which is toxic to rapidly dividing immature T lymphocytes (lead to dysfunction of T, B, and natural killer (NK) cells). o RAG Mutation- Recombinase-activating genes Immune System Module (RAG) defect blocks the development of T and B cells. ◤ o Jak3 mutation- Jak3, an intracellular kinase mutation is another way of blocking the cytokine receptor signalling. o Class II MHC deficiency-Mutations that impair Immune System Module the expression of class II MHC molecules prevent the development of CD4+ T cells. This condition is also called the bare lymphocyte syndrome. ◤ ▪ Infections- Affected infants are susceptible to severe recurrent infections by a wide array of pathogens, including Candida, Pneumocystis, cytomegalovirus, and Pseudomonas. ▪ Treatment- Bone marrow transplantation. Gene therapy replacing the mutated genes has been successful in X linked cases. Immune System Module T cell B cell Viral infection Fungal infection Bacterial infection Protozoal infection Severe Combined Immuno Deficiency (SCID) X-linked Agammaglobulinemia (XLA) Common Variable Immunoglobin Deficiency (CVID) Immune System Module ◤ Wiskott-Aldrich syndrome (WAS) ▪ X-linked recessive disease. ▪ Characterized by immunodeficiency thrombocytopenia, eczema. ▪ Severity of WAS increases with age. ▪ First manifests itself by defective responses to bacterial polysaccharides and by lower IgM levels. ▪ with o IgG levels are usually normal. o Paradoxically the levels of IgA and IgE are often elevated. Immune System Module Other T and B cell responses are normal initially, but with increase of age, there are recurrent bacterial infections and a gradual loss of humoral and cellular responses. ◤ ▪ Prone to develop non-Hodgkin B-cell lymphomas. ▪ Bloody diarrhea secondary to thrombocytopenia. ▪ Pathogenesis: o Genetic defect is due to a mutation in the gene encoding Wiskott-Aldrich syndrome protein (WASP) present in precursor lymphoid cells of bone marrow. o Impaired CD43 glycoprotein expression o Cytoskeletal glycoprotein (sialophorin or CD43), required for actin polymerization. Immune System Module ◤ Ataxia Telangiectasia Immune System Module ▪ Difficulty in maintaining balance while walking (cerebellar ataxia) ▪ Appearance of broken capillaries (telangiectasia) in the eyes and choreoathetoid movements (usually noticed in infancy). ▪ Deficiency of IgA and sometimes IgE. ▪ Profound sinopulmonary infections ▪ Primary defect - ATM kinase involved in regulation of the cell cycle. ◤ ▪ DISORDERS OF PHAGOCYTOSIS Chronic granulomatous disease (CGD) Pathogenesis: o Involves inherited defects in the gene encoding components of oxidase system. o E.g. Nicotinamide adenine dinucleotide phosphate (NADP) oxidase of phagocyte which breaks down hydrogen peroxide to generate free oxygen radicals (O2-) that are involved in microbial killing. o Decreased oxidative burst which predisposes to recurrent bacterial infections. CGD is a genetic disease that runs in family in two forms: Immune System Module ▪ X linked form (more common, 70%) - membrane component of phagocyte oxidase is defective. ▪ Autosomal recessive form- cytoplasmic component of phagocyte oxidase is defective. ▪ Manifestations- o Bacteria involved in the recurrent infections are catalase positive; pyogenic pathogens such as staphylococci, Pseudomonas and coliforms. o Excessive inflammatory reactions that result in gingivitis, swollen lymph nodes, and non-malignant granulomas (lumpy subcutaneous cell masses). ▪ Diagnosis- Neutrophil function test: Immune System Module o Nitroblue tetrazolium reduction test (NBT) is used for screening to detect deficiency of NADPH oxidase activity. o Dihydrorhodamine (DHR) testing assesses the production of superoxide radicals by measuring the conversion of DHR to rhodamine, a fluorescent green compound that can be detected on flow cytometry. ◤ Chediak-Higashi syndrome Immune System Module ▪ Autosomal recessive disease. ▪ Defective fusion of phagosomes and lysosomes in phagocytes which leads to increased susceptibility to recurrent and severe pyogenic infections. ▪ Abnormalities in melanocytes leading to albinism (lack of skin and eye pigment) ▪ Abnormalities in cells of the nervous system (associated with nerve defects), and ▪ Platelets abnormalities, causing bleeding disorders. ▪ Aggressive but non-malignant infiltration of organs by lymphoid cells. Infant with Chediak-Higashi syndrome presenting with hypomelanotic skin and white hair with a metallic sheen. From Carden et al, Br J Ophthal, 1998, 82:189-195, with permission from BMJ ◤ ▪ Pathogenesis: o Mutation in a protein called LYST (regulate lysosomal trafficking). Immune System Module o Impairs the targeting of proteins to secretory lysosomes, which makes them unable to lyse bacteria. o Phagocytes from patients with this immune defect contain giant granules but do not have the ability to kill bacteria. Leukocyte adhesion deficiency (LAD) ▪ Autosomal recessive disorder. ▪ Defect in the adhesion of leukocytes which results in poor leukocyte chemotaxis particularly neutrophil, inability to form pus and neutrophilia. Delayed separation of the umbilical cord. Predisposes to various infections Immune System Module o Leukocyte adhesion deficiency 1- Mutations in β2 integrin subunit (CD18), of the leukocyte cell adhesion molecule (chromosome 21). o Leukocyte adhesion deficiency 2- Mutations in fucosyltransferase required for synthesis of sialylated oligosaccharide which is a selectin ligand. ◤ Job’s Syndrome (Hyper IgE syndrome) ▪ eczema Characterized by eosinophilia Immune System Module ▪ Defect in neutrophil chemotaxis. ▪ Most cases are sporadic, but some familial cases of Hyper IgE Syndrome have been reported, with either an autosomal dominant (AD) or autosomal recessive (AR) mode of inheritance. recurrent staphylococcal skin abscesses, recurrent lung infections (pneumatocele) high serum levels of IgE. ◤ Schwachman's syndrome ▪ Rare congenital disorder characterized by neutropenia, exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal abnormalities, and short stature. Immune System Module ◤ Complement deficiency ▪ SLE commonly develops in individuals deficient in an early component of the classical pathway (ie, C1q, C1r, C1s, C4, and C2). ▪ C1 inhibitor deficiency — gives rise to hereditary angioedema ▪ C3 deficiency_ Complete deficiency of C3, the major opsonin of the complement system, results in severe, recurrent infections with encapsulated bacteria that begin shortly after birth ▪ C5-C9 deficiency_A deficiency of a component of the membrane attack complex (MAC, C5-C9) is associated with infection by Neisseria species (especially the meningococcus), Immune System Module ▪ Plasma factors H and I regulate C3 and a complete deficiency of either factor allows the alternative pathway to fire to exhaustion and thereby consume C3 - (recurrent infections) ◤ SECONDARY IMMUNODEFICIENCIES ▪ Secondary effects of other diseases such as- Immune System Module o Malnutrition (due to inadequate immunoglobulin synthesis) o Aging (suppression of immune system with age) o Patients with several infections that supresses immune system causing lymphocyte depletion, e.g. HIV (human immunodeficiency virus) infection. o Underlying cancers (particularly those of the bone marrow and blood cells (leukemia, lymphoma, multiple myeloma), o Underlying proteinuric renal diseases– leads to loss of immunoglobulins o Sarcoidosis o Patients on immunosuppressive medications o Patients receiving chemotherapy or radiation therapy for malignancy