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Diseases of Immunity Dr . HALA Badawi The Immune System 1. 2. The immune system is composed of two components: Humoral immunity, mediated by soluble antibody proteins. Cellular immunity, mediated by lymphocytes. The Immune System CELLULAR T ymphocytes HUMORAL B lymphocytes Cells of the Immune System T- Lymphocytes B- Lymphocytes Macrophages Dendritic Cells Natural Killer (NK) Cells Cells of the Immune System T Lymphocytes T lymphocyte constitute 60 to 70% of the lymphocytes in circulating blood. Present in the periarteriolar sheaths of the spleen and interfollicular zones of the lymph nodes Cells of the Immune System T Lymphocytes Each T cell has a specific T-cell receptor (TCR) TCRs are linked to 5 clusters of polypeptide chains, called the CD3 complex Cells of the Immune System T Lymphocytes In addition, T cells express other associated molecules, (CD4 and CD8). These two molecules are expressed on distinct T-cell subsets and serve as coreceptors for T-cell stimulation. Cells of the Immune System T Lymphocytes CD4 is expressed on about 60% of mature T cells, Whereas CD8 is expressed on about 30% of T cells. In normal healthy individuals, the CD4/CD8 ratio is therefore about 2:1. During antigen recognition, CD4 molecules on T cells bind to class II MHC molecules on selected APCs; and CD8 binds to class I MHC molecules. Cells of the Immune System CD4+ T cells are called "helper" T cells because they secrete soluble molecules (cytokines) that influence all other cells of the immune system. CD 4 T cells are divided into two types (T- helper1 & T-helper 2) The CD 8 T cells are called cytotoxic cells. They play an important role in directly killing virus-infected or tumor cells. Cells of the Immune System 2- B Lymphocytes B lymphocytes comprise 10% to 20% of the circulating peripheral lymphocyte population. They are also present in bone marrow, in peripheral lymphoid tissues (lymph nodes, spleen, and tonsils) After stimulation, B cells form plasma cells that secrete immunoglobulins, which in turn are the mediators of humoral immunity. There are five basic immunoglobulin IgG, IgM,IgA (95% of circulating antibodies) IgE and IgD. •B cells recognize antigen via B-cell receptor (BCR) •As with T cells, each BCR has a unique antigen specificity, derived from somatic rearrangements of immunoglobulin genes IgM, IgG, IgA, IgE, IgD B – Cell Receptors Cells of the Immune System Macrophages • Macrophages (along with dendritic cells, below) express class II MHC and are therefore central players in the processing and presentation of antigen to CD4+ helper T cells. Because T cells (unlike B cells) cannot be triggered by free antigen, presentation by macrophages or other antigen presenting cells (APCs) is obligatory for induction of cell-mediated immunity. Macrophages produce many cytokines that not only influence T- and B-cell function but also affect other cell types, including endothelium and fibroblasts. Macrophages phagocytose (and ultimately kill) microbes coated by antibody and/or complement ; consequently, they are important effector elements in humoral immunity. • • Cells of the Immune System Dendritic Cells : They are the most potent antigen presenting cells (APC), express high levels of MHC class II, and presenting antigens to CD4+ T cells . They are widely distributed, occurring in lymphoid tissues and in the interstitium of many non-lymphoid organs, such as the heart and lungs. In the epidermis are also called Langerhans cells. Cells of the Immune System Natural Killer (NK) Cells NK cells are larger than small lymphocytes and comprise 10 to 15% of peripheral blood lymphocytes. These cells are able to kill a variety of tumor cells, virally infected cells, and some normal cells, without previous sensitization. These cells are classified as part of the inborn immune system that is the first line of defense against a variety of attacks. Major Histocompatibility Complex They are genes located on chromosome 6 They are present on all nucleated cells and are classified into 3 classes Major Histocompatibility Complex Histocompatibility Molecules (MHC) are critical element in inducing and regulating normal immune function.( also known as the HLA complex). They are responsible for presenting antigens for T cells, as T cells (unlike B cells) can only recognize antigens, through MHC molecules; (MHC restriction). The MHC (HLA) system is highly polymorphic; that is, there are several alternative forms of a gene at each locus. Major Histocompatibility Complex MHC gene products fall into three categories: Class I MHC molecules are present on all nucleated cells, presenting intracellular infection like viruses and can be detected by cytotoxic T CD8 cells. Class II MHC molecules expressed mainly on APCs (monocytes, macrophages, and dendritic cells). MHC II molecules bind to peptides derived from proteins (e.g., those derived from extracellular bacteria) synthesized outside the cell. which recognize CD4 cells.. Class III proteins include some of the complement components. Significance of Histocompatibility Molecules. The significance of MHC polymorphism is clear in transplantation. MHC molecules of the graft evoke both humoral and cell-mediated responses, eventually leading to graft destruction. Because the severity of the rejection reaction is in large part related to the degree of donor and recipient MHC (HLA) disparity, HLA typing is of clinical significance in the selection of appropriate donorrecipient combinations. Some diseases are related to HLA, e.g. ankylosing spondylitis and several postinfectious arthropathies, all associated with HLA-B27. CYTOKINES, The Soluble Mediators of the Immune System Cytokines are polypeptides that are secreted mainly by lymphocytes and APCs. Cytokines mediate their effects by binding to specific receptors on their target cells. For example, IL-2 activates T cells by binding to IL-2 receptors. Blockade of the receptor prevents T-cell activation. Cytokines induce their effects in three ways: autocrine, paracrine and endocrine effects. CYTOKINES, The Soluble Mediators of the Immune System Many individual cytokines are produced by several different cell types. For example, IL-1 and TNF can be produced by any cell. The cytokines can act on many cell types, causing many different effects. For example, IL-2 is a T-cell growth factor; however, it is also regulate the growth and differentiation of B cells and NK cells. Multiple cytokines may induce similar effects, for example, IL-1 and TNF have very similar effectors profiles HYPERSENSITIVITY REACTIONS Although immune activation are generally protective against infections (and to some extent tumors), such responses may also potentially damage host tissues The term hypersensitivity is used to describe immune responses which are damaging rather than helpful to the host The hypersensitivity reactions are subdivided into four types: Type I disease : Allergy and Anaphylaxis Type II disorders: Antibody Dependent. Type III disorders: Immune complex diseases. Type IV disorders: delayed-type hypersensitivity Type I Hypersensitivity (Allergy and Anaphylaxis) IgE-mediated hypersensitivity Time: 2-30 mins Mechanism: results from IgE antibodies bound to mast cells, when these IgE molecules bind their specific antigen (allergen), they are triggered to release vasoactive mediators that in turn affect vascular permeability and smooth muscle contraction in various organs. Examples: 1-Local reaction: (e.g., seasonal rhinitis, or hay fever) andasthma) 2-Systemic disorder (anaphylaxis). Type I Hypersensitivity Chemical mediators of type I Hypersensitivity Clinical Manifestations of Type I Hypersensitivity Systemic anaphylaxis results from systemic (parenteral) administration of protein antigens or drugs (e.g., bee venom or penicillin). Within minutes of an exposure in a sensitized host, itching, urticaria , skin erythema, followed by bronchoconstriction and Laryngeal edema that cause respiratory obstruction. In addition, vomiting, abdominal cramps, and diarrhea. Without immediate intervention, there may be systemic vasodilation (anaphylactic shock), and the patient may die within minutes. Local reactions occur when the antigen is confined to a particular site by the route of exposure, such as Skin (contact), causing urticaria & eczema GIT (ingestion), causing diarrhea in food allergy Lung (inhalation), causing bronchoconstriction as in asthma and hay fever. Type II Hypersensitivity (Antibody Dependent) Antibody-mediated cytotoxic hypersensitivity Time: 5-8hrs Mechanism: is mediated by antibodies directed against target antigens on the surface of cells or other tissue components Examples: Blood transfusion reactions, Haemolytic disease of the newborn, Autoimmune Haemolytic anaemia Type II, Complement dependent reaction that lead to cell lyses or render them susceptible to phagocytosis B - Antibody dependent cell mediated cytotoxicity (ADCC) IgG coated target cells are killed by cell bear Fc receptor for IgG (NK cells) C- Anti receptor antibodies, acetyle receptor antibodies, impair the neuromuscular transmission in mythenia gravis Type III Hypersensitivity (Immune Complex-Mediated) Time: 2-8hrs Mechanism: is mediated by the deposition of antigenantibody (immune- complexes), followed by complement activation and accumulation of polymorphonuclear leukocytes. PMN degranulation caused damages of tissue Immune complexes can involve exogenous antigens such as bacteria and viruses or endogenous antigens such as DNA. Examples: systemic when complexes are formed in the circulation and are deposited in multiple organs or localized to particular organs (e.g., kidneys, joints, or skin). Type III Hypersensitivity (Immune Complex-Mediated) Type IV Hypersensitivity (Cell-Mediated) Time: 24-72hrs Mechanism: Type IV hypersensitivity is mediated by sensitized T cells and is subdivided into two types: 1. Delayed-type hypersensitivity, initiated by CD4+ T cells 2. Direct cell cytotoxicity, mediated by CD8+ T cells. Type IV Hypersensitivity 1- Delayed-type hypersensitivity, initiated by CD4+ T cells, which secrete cytokines, leading to recruitment of macrophages forming granulomas Granuloma Type IV Hypersensitivity (Cell-Mediated) Direct cell cytotoxicity, mediated by CD8+ T cells. Mechanism: Sensitized CD8+ T cells kill antigen-bearing target cells. Class I MHC molecules bind to intracellular viral peptides and present them to CD8+ T lymphocytes to kill them. The CD8+ effector cells, called cytotoxic T lymphocytes (CTLs), play a critical role in resistance to virus infections. Examples: Contact dermatitis. Type IV hypersensitivity, Direct cell cytotoxicity, Mediated by CD8+ T cells. CTL Killing Transplant Rejection Rejection of organ transplants is involving both cell- and antibodymediated hypersensitivity responses of the host directed against histocompatibility molecules on the donor graft. Transplant Rejection Clinical Types of Rejection: HYPERACUTE REJECTION: occurs within minutes to a few hours after transplantation in a presensitized host (preformed antibodies). ACUTE REJECTION. Acute rejection may occur within days to weeks of transplantation in a non-immunosuppressed host, acute rejection is a combined process to which both cellular and humoral mechanisms CHRONIC REJECTION. chronic rejection presents late after months to years with a progressive renal dysfunction and is characterised by thickened BVs , fibrosis, and loss of renal tissue. Caused by humoral and cell-mediated mechanisms. It is hard to prevent and hard to treat. Types of Organ Transplantation Kidney Most common transplanted organ Diabetes, glomerulonephritis, congenital disorders Complications: • Rejection • post-transplant malignancy Types of Organ Transplantation Bone Marrow Leukemia, lymphoma Find living donor (easy) that matches (hard) Massive chemo/radiation first Complications: Graft versus host reaction (GVHD) • Donor T cells see recipient as foreign! • Attack skin, GI, liver • Treat with immunosuppressives • Or, partially deplete donor marrow of T cells Immunologic Tolerance and Autoimmunity “Tolerance” = unresponsiveness to an antigen Selfe Tolerance: Is a lack of immune responsiveness to one's own tissue antigens. Autoimmunity implies loss of self-tolerance Autoimmune Diseases Autoimmune diseases range from: 1-Localized: specific immune responses against one particular organ or cell type and result in localized tissue damage. Examples: 1. Hashimoto thyroiditis, 2. Autoimmune hemolytic anemia, 3. Autoimmune atrophic gastritis, 4. Myasthenia gravis 5. Graves disease Autoimmune Diseases 2-Multisystem diseases: characterized by lesions in many 1. 2. 3. 4. organs and associated with a multiplicity of auto-antibodies or cell-mediated reactions. Examples, Systemic lupus erythematosus, Rheumatoid arthritis, Sjogren syndrome Inflammatory myopathy In these diseases, the pathologic changes occur principally within the connective tissue and blood vessels of the various organs involved, and called collagen vascular diseases or connective tissue diseases Autoimmune Diseases Lupus Erythematosus Typical patient: young woman with butterfly rash Symptoms unpredictable (relapsing/remitting) Multisystem effects: Kidney (renal failure) Skin (“butterfly rash”) CNS (focal neurologic deficits) Joints (arthritis) Heart (peric Autoimmune Diseases Lupus Erythematosus Etiology and Pathogenesis. The main defect in SLE is a failure to maintain self-tolerance. There is generation of a wide array of autoantibodies that can damage tissue either directly or in the form of immune complex deposits 1- Antinuclear Antibodies (ANAs). 2- Anti-double-stranded DNA antibodies SLE, butterfly rash Discoid lupus Autoimmune Diseases Rheumatoid Arthritis •Female patient with aching, stiff joints, especially in morning •Symmetric joint swelling (mostly small joints) •Fingers: ulnar deviation and swan-neck deformities •Rheumatoid skin nodules •Systemic symptoms (skin, heart, vessels, lungs) Autoimmune Diseases Rheumatoid Arthritis Rheumatoid factor: • Circulating IgM antibody • Directed against patient’s OWN IgG! • Forms IgM-IgG immune complexes, which deposit in joints and cause badness •Present in 80% of patients Autoimmune Diseases Rheumatoid Arthritis •Chronic synovitis with pannus formation •synovial cell proliferation •Inflammation •granulation tissue Autoimmune Diseases Rheumatoid Arthritis Autoimmune Diseases Sjögren syndrome • Inflammatory disease of salivary and lacrimal glands •Female between 35-45 •T cells react against some Ag (self? viral?) in gland; gland gets destroyed • Dry eyes (Keratoconjunctivitis sicca) •Dry mouth (Xerostomia ) • Increased risk of lymphoma Autoimmune Diseases Sjögren syndrome Immune Deficiency Diseases Congenital Immune Deficiency Diseases X-linked agammaglobulinemia Common variable immunodeficiency Isolated IgA deficiency Hyper-IgM syndrome DiGeorge syndrome Severe combined immunodeficiency Acquired Immune Deficiency Disease (Aids) ACQUIRED IMMUNODEFICIENCY SYNDROME AIDS is a retroviral disease characterized by profound immunosuppression that leads to: 1. Opportunistic infections, 2. Secondary neoplasms, 3. Neurologic manifestations ACQUIRED IMMUNODEFICIENCY SYNDROME Five groups of adults are at risk for developing AIDS: 1. Homosexual or bisexual men (57% of cases) 2. Intravenous drug abusers (25% of cases) 3. Hemophiliacs, who received large amounts of infected factor VIII concentrates (0.8% of cases) 4. Recipients of blood and blood components , who received transfusions of HIV-infected whole blood or components (e.g., platelets, plasma) (1.2% of cases) ACQUIRED IMMUNODEFICIENCY SYNDROME In approximately 6% of cases, the risk factors cannot be determined Close to 2% of all AIDS cases occur in pediatric population In this group, more than 90% have resulted from transmission of the virus from mother to child. The remaining 10% are hemophiliacs and others who received infected blood or blood products ACQUIRED IMMUNODEFICIENCY SYNDROME Aetiology: AIDS is caused by human immunodeficiency virus (HIV Two genetically different but related forms of HIV, called HIV-1 and HIV-2, have been isolated from patients with AIDS HIV-1 is the most common type associated with AIDS in the United States, Europe, and Central Africa HIV-2 causes a similar disease principally in West Africa ACQUIRED IMMUNODEFICIENCY SYNDROME Aetiology: The HIV-1 virion is spherical and contains an electron-dense, coneshaped core surrounded by a lipid envelope derived from the host cell membrane The virus core contains 1. The major capsid protein p24 2. Nucleocapsid protein p7/p9 3. Two copies of genomic RNA, and 4. The three viral enzymes (protease, reverse transcriptase, and integrase) ACQUIRED IMMUNODEFICIENCY SYNDROME Aetiology: p24 is the most readily detected viral antigen and, as such, is the target for the antibodies that are used for the diagnosis of HIV infection by (ELISA) The viral core is surrounded by a matrix protein called p17, which lies underneath the virion envelop Studding the viral envelope are two viral glycoproteins, gp 120 and gp 41, which are critical for HIV infection of cells ACQUIRED IMMUNODEFICIENCY SYNDROME PathogenesisThere are two major targets of HIV: The immune system and the central nervous system Initially, HIV-1 infects T cells and macrophages directly or is carried to these cells by Langerhans cells CD4 molecule is, a high-affinity receptor for HIV. This explains the selective tropism of the virus for CD4+ T cells and other CD4+ cells, particularly monocytes /macrophages and Langerhans cells/dendritic cells Binding to CD4 is not sufficient for infection, however HIV gp120 must also bind to other cell surface molecules for entry into the cell After fusion, the virus core containing the HIV genome enters the cytoplasm of the cell ACQUIRED IMMUNODEFICIENCY SYNDROME Pathogenesis There are two major targets of HIV: The immune system and the central nervous system It is important to note that although HIV-1 can infect resting T cells, the initiation of productive infection occurs only when the infected cell is activated by an exposure to antigens or cytokines It is obvious therefore that physiologic stimuli that promote activation and growth of normal T cells lead to the death of HIVinfected T cells So the productive infection of T cells is the mechanism by which HIV causes lysis of CD4+ T cells ACQUIRED IMMUNODEFICIENCY SYNDROME Pathogenesis There continues a gradual erosion of CD4+ cells by productive infection Ultimately, CD4+ cell numbers decline, and the patient develops clinical symptoms of full-blown AIDS Macrophages are also parasitized by the virus early; they are not lysed by HIV-1, and they may transport the virus to tissues, particularly the brain ACQUIRED IMMUNODEFICIENCY SYNDROME Pathogenesis HIV infection of macrophages has three important significans: They act as virus factory and reservoir. Macrophages provide a vehicle for HIV to be transported to various parts of the body, particularly the nervous system. In late stages of HIV infection, when the CD4+ T-cell numbers decline greatly, macrophages may be the major site of continued viral replication. MAJOR ABNORMALITIES OF IMMUNE FUNCTION IN AIDS 1. Lymphopenia 2. Decreased T-Cell Function 3. Polyclonal B-Cell Activation 4. Altered Monocyte or Macrophage Functions Natural History of HIV Infection Three phases reflecting the dynamics of virus-host interaction can be recognized: 1. An early, acute phase 2. A middle, chronic phase 3. A final, crisis phase In the absence of treatment, most but not all patients with HIV infection progress to AIDS after a chronic phase lasting from 7 to 10 years Natural History of HIV Infection Exceptions to this typical course are: – Long-term nonprogressors: patient remains asymptomatic for 10 year or more, with stable CD4+ counts and low level of plasma viremia. – Rapid progressors. in those the middle, chronic phase is shortened to 2 to 3 years after primary infection Infection & Neoplasms Protozoal and Helminthic Infections – Pneumocytosis Carnii (pneumonia or disseminated infection) – Toxoplasmosis (pneumonia or CNS infection) Fungal Infections – Candidiasis (esophageal, tracheal, or pulmonary) – Cryptococcosis (CNS infection) – Coccidioidomycosis (disseminated) – Histoplasmosis (disseminated) Infection & Neoplasms Bacterial Infections – Mycobacteriosis (atypical, e.g., M. avium-intracellulare, disseminated or extrapulmonary; M. tuberculosis, pulmonary or extrapulmonary) Nocardiosis (pneumonia, meningitis, disseminate) Salmonella infections (disseminated) – – Viral Infections – – – – Cytomegalovirus (pulmonary, intestinal, retinitis, or CNS infections) Herpes simplex virus (localized or disseminated) Varicella-zoster virus (localized or disseminat) Progressive multifocal leukoencephalopathy Infection & Neoplasms Neoplasms Kaposi sarcoma B-cell non-Hodgkin lymphomas Primary lymphoma of the brain Invasive cancer of uterine cervix Can there be a cure ?? Antiretroviral drugs: Virus persists in the lymphoid tissue Vaccination: High degree of polymorphism At present, therefore, prevention and effective public health measures remain the mainstay in the fight against AIDS Amyloidosis Amyloidosis is the term used for the abnormal deposition of proteinaceous material in tissues interstitium Can occur in a spectrum of clinical disorders with progressive accumulation, it encroaches on and produces pressure atrophy of adjacent cells Amyloidosis Nature Physical nature Amyloid is composed largely of non-branching fibrils 7.5 to 10 nm in width Arranged in a characteristic crossed B-pleated sheet conformation this structural organization is seen regardless of the clinical setting or the chemical composition is responsible for the distinctive staining and optical properties of amyloid Amyloidosis Nature Chemical nature Three distinct forms of amyloid proteins are most common: 1. 2. 3. AL (amyloid light chain) is derived from plasma cells and contains immunoglobulin light chains AA (amyloid-associated) is a unique non-immuno globulin protein synthesized by the liver Aft amyloid is found in the cerebral lesion of Alzheimer disease Amyloidosis Nature Chemical nature The AL protein is made up of complete immunoglobulin light chains, the terminal fragments of light chains, or both AL type is produced by immunoglobulin-secreting cells its deposition is associated with some form of monoclonal B-cell proliferation Amyloidosis Nature Chemical nature The AA amyloid fibril is composed of a protein that derive from a larger serum precursor synthesized in the liver called SAA (serum amyloid-associated) protein AA proteins are typically deposited in the setting of chronic inflammatory states Amyloidosis Nature Chemical nature Other forms: Transthyretin (TTR) B2-microglobulin, a component of the MHC class I molecules and a normal serum protein Pathogenesis Amyloidosis Classification SYSTEMIC On clinical grounds PRIMARY SECONDARY LOCALIZED FAMILIAL/HEREDITARY Amyloidosis Primary Amyloidosis usually systemic in distribution and is of the AL type this is the most common form of amyloidosis The best example in this category is amyloidosis associated with multiple myeloma, a malignant neoplasm of plasma cells Amyloidosis Reactive Systemic Amyloidosis (Secondary Amyloidosis) Systemic in distribution and is of the AA type Cell injury occurring in a spectrum of infectious and non-infectious chronic inflammatory conditions Tuberculosis, bronchiectasis, and chronic osteomyelitis Rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease Chronic skin infections Renal cell carcinoma and Hodgkin disease Amyloidosis Heredofamilial Amyloidosis The best characterized is an autosomal recessive condition called familial Mediterranean fever It is associated with widespread tissue involvement indistinguishable from reactive systemic amyloidosis The amyloid fibril proteins are made up of AA proteins Amyloidosis Localized Amyloidosis Amyloid deposits are limited to a single organ or tissue without involvement of any other site in the body The deposits may produce grossly detectable nodular masses or be evident only on microscopic examination Nodular (tumor-forming) deposits of amyloid are most often encountered in the lung, larynx, skin, urinary bladder, tongue, and the region about the eye Amyloidosis Morphology No specific findings for the previous categories, however: Secondary amyloidosis more often involves: kidneys, liver, spleen, lymph nodes, adrenals, and thyroid, as well as many other tissues are typically affected Primary amyloidosis, more often involves the heart, gastrointestinal tract, respiratory tract, peripheral nerves, skin, and tongue cannot reliably be distinguished by its organ distribution Amyloidosis Morphology Grossly: Organ is enlarged, grayish in color, waxy firm in consistency Microscopically: amyloid appears as deposition of an amorphous, eosinophilic, hyaline extracellular substance Amyloidosis Kidney Heart Amyloidosis Diagnosis Diagnosis is by Congo red stain; apple green birefringence upon examination under polarized light Confirmation can be obtained by electron microscopy, which reveals amorphous non-oriented thin fibrils AA, AL, and transthyretin amyloid can also be distinguished by specific immunohistochemical staining Amyloidosis Morphology