Immunodeficiency States PDF

Immunodeficiency states Prof. Salim Bafakeer Learning objectives  Explain the immunodeficiency states.  Immunodeficiency disorders  The immunodeficiency disorders are a diverse group of illnesses, as a result of one or more abnormalities of the immune system, p...

Immunodeficiency states Prof. Salim Bafakeer Learning objectives  Explain the immunodeficiency states.  Immunodeficiency disorders  The immunodeficiency disorders are a diverse group of illnesses, as a result of one or more abnormalities of the immune system, predispose a person to infection.  The abnormalities of the immune system can involve absence or malfunction of blood cells (lymphocytes, granulocytes, monocytes) or soluble molecules (antibodies, complement components).  Immune deficient states can be subdivided into Primary immune deficiency: diseases due to a hereditary or intrinsic defect in the immune system. Secondary ( Acquired) immune deficiency: as the result of infection, such as HIV, administration of cytotoxic drugs, as with cancer chemotherapy, or metabolic states, such a malnutrition, that compromise the immune system.  Primary Immunodeficiencies  Primary immunodeficiency diseases (PIDs) comprise a heterogeneous group of disorders characterized by defects in development and/or function of the immune system.  PIDs result from intrinsic defects in cells and mediators of the innate and adaptive immune system.  The classification of PIDs is based on the nature of the underlying immunological defect.  Defects in Innate Immunity  Abnormalities in two components of innate immunity, phagocytes and the complement system, are important causes of immunodeficiency.  Phagocytic cell disorders include defects in development and/or function of myeloid cells (granulocytes, macrophages).  Complement deficiencies are represented by genetically- determined defects of functional or regulatory components of the complement system.  Quantitative disorder  Congenital agranulocytosis (Kostmann syndrome): Defect in the gene inducing G-CSF (granulocyte colony stimulating factor). Patients have a decrease in the neutrophil count. This is due to a defect in the myeloid progenitor cell differentiation into neutrophils. These patients are treated with granulocyte-macrophage colony stimulating factor (GM-CSF) or G-CSF Features: pneumonia, otitis media, gingivostomatitis, perineal abscesses.  Phagocytic dysfunction  Primary or intrinsic phagocytic disorders are related to enzymatic deficiencies within the metabolic pathway in the phagocyte, necessary for killing bacteria. Chronic granulomatous disease – due to deficiency of NADPH oxidase Myeloperoxidase deficiency Chediak –Higashi syndrome Lazy Leucocyte syndrome  Chronic granulomatous disease  Chronic granulomatous disease is an X-linked disorder which manifests in the first two years of life.  Caused by mutations in genes encoding subunits of the enzyme phagocyte NADPH oxidase, which catalyzes the production of microbicidal reactive oxygen species in lysosomes. Affected neutrophils and macrophages are unable to kill the microbes they phagocytose.  The result is that intracellular killing of bacteria and fungi is impaired.  Patients with this disease are very susceptible to opportunistic infections with certain bacteria and fungi.  Recurrent infections with catalase-positive bacteria, such as staphylococci, are common in these patients.  Catalase- producing bacteria can degrade hydrogen peroxide, which is an alternative source of free radicals that CGD leukocytes could use to kill bacteria.  Immune system tries to compensate for this defective microbial killing by calling in more macrophages.  Collections of macrophages accumulate around foci of infections to try to control the infections. These collections resemble granulomas, giving rise to the name of this disease.  Specific enzyme deficiencies  Glucose-6-phosphate dehydrogenase is completely lacking in the leukocyte, and produces a disease syndrome similar to chronic granulomatous disease. The disease has a later onset, affects both males and females and haemolytic anaemia is present.  Deficiency of leukocyte myeloperoxidase, needed for normal intracellular killing leads to recurrent candidial and staphylococcal infections. The leukocyte respiratory burst and super oxide anion formation are, however, normal.  Chediak-Higashi Syndrome  Chediak-Higashi syndrome is a multi system autosomal recessive disorder characterized by:  Recurrent bacterial infections, hepatosplenomegaly, central nervous system abnormalities and a high incidence of lymphoreticular cancer.  The basic defect is abnormal intracellular killing of organisms due to defective fusion of phagosomes and lysosomes; and large granular inclusions in white blood cells composed of abnormal lysosomes.  Abnormalities in melanocytes leading to albinism (lack of skin and eye pigment): due to inability of melanocytes to transfer pigment into Keratinocytes & other epithelial cells.  Platelets abnormalities: causing bleeding disorders due to platelet dysfunction CHEDIAK-HIGASHI SYNDROME  Lazy Leukocyte Syndrome  Patients with defective neutrophil chemotaxis in association with neutropenia.  Such patients are susceptible to severe bacterial infections.  Complement Deficiency States  Variety of complement deficiencies and abnormalities of complement function have been associated with increased susceptibility to infection.  Complement factors are necessary for opsonization, bacterial killing and chemotaxis  Deficiencies in complement are inherited as autosomal traits; heterozygous individuals have half the normal level of a given component. For most components, this is sufficient to prevent clinical disease.  Early components of complement are particularly important in generating the opsonin, C3b  Patients with deficiencies of C1, 4, or 2 from the classical pathway or with deficiency in C3 itself have increased infections with encapsulated organisms (S. pneumoniae, Streptococcus pyogenes, H. influenza)  Deficiencies of the late complement components (C5–C9) interfere with the generation of the membrane attack complex (MAC).  The MAC is directly lytic and responsible for the primary defense against Gram-negative bacteria  Defects in Lymphocyte Maturation  Antibody deficiencies reflect impaired function of B lymphocytes as a result of intrinsic B cell abnormalities or of defects in T lymphocytes that affect activation and terminal maturation of B lymphocytes  Combined immunodeficiencies are characterized by impaired development and/or function of T lymphocytes, and functional B cell abnormalities  Defects in B cell function  Defective antibody responses are due to failure of B cell function, as occurs in X-linked agammaglobulinemia, or failure of proper T cell signals to B cells, as occurs in hyper-IgM (HIgM) syndrome.  Defects of B cells result in impaired antibody production.  Patients affected with these disorders present recurrent pyogenic infections, recurrent infections of upper and lower respiratory tract, particularly pneumonia and sinusitis as well as the ear (otitis media).  Diverse spectrum of diseases ranging from: Complete absence of B-cells, Plasma cells and Immunoglobulins to selective absence of certain immunoglobulin classes  X-linked (Bruton) Agammaglobulinemia  The gene governing the disorder has been localized to the long arm of the X chromosome.  Results from a virtual absence of B cells in young boys; thus, no antibody in the circulation; serum IgA, IgM, IgD and IgE, and IgG levels are extremely low; Plasma cells do not develop and antibody responses are absent.  Pre-B cells are present in the bone marrow of patients indicating a failure of differentiation into mature B cells.  The molecular basis of X-linkd agammaglobulinemia has been shown to be due to the lack of a cytoplasmic tyrosine kinase, which prevents B cell maturation, and production of immunoglobulins.  The result is a profound inability to respond to extracellular bacterial infection, so unusual susceptibility to pyogenic organisms, chronic recurrent upper respiratory tract bacterial infections are very common.  Because infants are born with IgG transferred from their mothers, the disease does not manifest until late in the first year of life. The effects of this condition usually appear in male infants between 9 months and 2 years of age  X-linked hyper-IgM syndrome  Characterized by defective B cell heavy-chain isotype (class) switching, so immunoglobulin M (IgM) is the major serum antibody, and by deficient cell-mediated immunity against intracellular microbes.  The disease is caused by mutations in the X chromosome gene encoding CD40 ligand (CD40L), the helper T cell protein that binds to CD40 on B cells, dendritic cells, and macrophages and thus mediates T cell–dependent activation of these cells.  Binding of CD40L to CD40 is also important to promote interaction between activated T cells and macrophages, which result in production of IFNγ and activation of macrophages against intracellular pathogens.  The switching from IgM to IgG and IgA in B cells depends on binding of the B cell's CD40 to CD40 ligand on T cells.  Failure of expression of functional CD 40 L on TH cells (No class switching)  Selective IgA deficiency  This is the most common antibody deficiency and results in chronic infections at mucosal surfaces; since IgA is the secretory antibody which protects these surfaces.  However, since IgG and IgM can compensate, to a significant degree, for the lack of IgA, this deficiency often goes unnoticed since it usually does not cause serious problems.  Defects in T cell function  Due to ineffective antigen presentation or immune recognition result in susceptibility to opportunistic infections.  Other abnormalities of T cells may also lead to immune dysregulation with autoimmunity or overactive immune responses.  Patients with T cell immunodeficiencies are extremely susceptible to opportunistic infections. They manifest with impaired delayed hypersensitivity responses.  Congenital thymic hypoplasia (Di George Syndrome)  Autosomal dominant trait.  The absence of the thymus leads to deficiency in cell- mediated immunity in affected children  Lack of T helper (Th) cells, Cytotoxic T cells (CTL) and T regulatory (Treg) cells.  B cells are present but T-dependent B cell responses are defective  Anti-viral and anti-fungal immunity impaired  These children do not exhibit delayed hypersensitivity reactions.  Severe combined immune deficiency (SCID)  SCID comprises a heterogeneous group of diseases in which both cell-mediated immunity and antibody production are defective  Results in no, or low numbers of functional B and T cells.  By far the most profound effect on the immune response is the lack of T cells.  Children with SCID are usually diagnosed in their first six months of life because of severe bacterial, viral and fungal infections  Individuals with SCID are susceptible to virtually every type of microbial infection (viral, bacterial, fungal, and protozoal), including opportunistic infections Primary Immunodeficiencies  Secondary (acquired)Immunodeficiencies  Major causes of secondary immunodeficiency include: Malnutrition Viral infection (e.g. HIV). Cancer metastases or leukemias, especially those involving bone marrow; Cancer treatments such as chemotherapy or irradiation; Corticosteroids: a type of immunosuppressant, are used to suppress inflammation due to various disorders, such as rheumatoid arthritis. Chronic disease: Immunodeficiency disorders may result from almost any prolonged serious disorder. For example, diabetes can result in an immunodeficiency disorder because white blood cells do not function well when the blood sugar level is high.  Malnutrition  Globally, malnutrition is the most common cause of immunodeficiency  Immune responses are significantly impaired when calories, macronutrients or any key micronutrients are in limiting supply, leaving the undernourished at increased risk for infection.  Severe protein – energy malnutrition (PEM) reduces the efficacy of the immune system.  Traces elements, iron, selenium, copper and zinc are important in immunity. Lack of these elements can lead to diminished neutrophil killing of bacteria and fungi, susceptibility to viral infections and diminished antibody responses.  Vitamins A, B6, C, E and also folic acid are important in overall resistance to infection. Carotenoids are antioxidants like vitamin C and E and can enhance NK cell activity, stimulate the production of cytokines and increase the activity of phagocytic cells  Immunodeficiency secondary to drug therapies  Immunomodulatory drugs can severely depress immune functions.  Cyclophosphamide, azathioprine and my cophenolate mofetil act directly on DNA or its synthesis.  Steroids causes circulating lymphocytopenia, Monocytopenia, Neutrophilia and inhibit cytokine synthesis.  T-cell activation and proliferation are inhibited by steroids.  Human immunodeficieny virus (AIDS)  Infection with human immunodeficiency virus (HIV) is second only to malnutrition in causing immune deficiency and is a significant cause of morbidity and mortality worldwide.  HIV is a retrovirus whose primary cellular targets upon infection are CD4 T cells, and macrophages.  Untreated, HIV leads to depletion of the immune system or acquired immunodeficiency syndrome (AIDS), leaving the host susceptible to fatal opportunistic infections.  Disease caused by normally non-pathogenic infections occur, as do cancers such as Kaposi’s sarcoma and non- Hodgkin’s lymphoma  HIV is primarily transmitted via sexual, contaminated needles/blood products, or vertically from mother-to-child during the perinatal period.  The immunopathologic effects of HIV infection are directly related to the interaction of the virus with a receptor (CD4 surface molecule) on CD4+ T cells or T helper cells. The CD4+ molecule is expressed also on the surface of monocytes, macrophages and microglial cells.  In addition to the CD4 receptor present in macrophages, monocytes, and T cells, macrophage tropic strains of HIV 1 also need the presence of a CCR5 receptor on the cell surface to cause infection.  Another receptor, CXCR4 a chemokine receptor enhances binding and internalisation of lymphotropic HIVHuman immunodeficiency virus (HIV) infection results in acquired immunodeficiency syndrome (AIDS), the most common severe acquired immunodeficiency disorder Thank you