Diseases of Immunity PDF

Diseases of Immunity By Dr. Yilkal A. Immuno pathology  Introduction  Hypersensitive reactions  Autoimmune disease  Immunodeficiency syndrome Introduction The immune system is vital for survival, because it protects us from pathogenic agents. Immune deficiencies render individuals e...

Diseases of Immunity By Dr. Yilkal A. Immuno pathology  Introduction  Hypersensitive reactions  Autoimmune disease  Immunodeficiency syndrome Introduction The immune system is vital for survival, because it protects us from pathogenic agents. Immune deficiencies render individuals easy prey to infections. But the immune system is itself capable of causing tissue injury and disease. Examples of disorders caused by immune responses include: allergies autoimmunity).  The normal immune response Immunity can be defined as protection from pathogenic agents. The mechanisms of immune system fall into two broad categories Innate immunity(natural/native) Adaptive immunity(adaptive/specific) Innate immunity -Innate immunity is always present, ready to provide defense against microbes and to eliminate damaged cells. The receptors and components of innate immunity have evolved to serve these purposes. Innate immunity functions in stages:  Recognition  Activation  Elimination Innate defense mechanisms: 1) Physical barriers Skin Urothelium Mucous membranes 2) Mechanical decontamination: Desquamation of surface cells together with adherent organisms Flushing of the urinary tract Mucous trapping and expulsion Coughing, sneezing, vomiting, intestinal downward propulsion 3) Anti microbial secretions: Lysozymes (muramidase) in sweat, tears, and saliva Acidity of sweat, gastric juice and vaginal secretion Unsaturated fatty acids in sebum and sweat Ig A in intestinal secretions 4) Phagocytic cells such as neutrophils & macrophages 5) NK cells, dendritic cells and mast cells 6) Plasma proteins including the proteins of the complement system and surfactants Reactions of innate immunity:  Inflammation: Cytokines and products of complement activation, as well as other mediators, are produced during innate immune reactions and trigger the vascular and cellular components of inflammation.  Antiviral defense: Type I interferons produced in response to viruses act on infected and uninfected cells and activate enzymes that degrade viral nucleic acids and inhibit viral replication, inducing what has been called an antiviral state. Adaptive immunity: Characterized by…. Specificity Diversity Memory Recruitment - It implies the generation of a specific cellular or humoral response to the infectious agent that can be either an active or a passive response 1)-Active immunity occurs when an individual mounts a cellular immune response or manufactures antibodies in response to an antigen i) Natural following previous infections or ii) Artificial by administration of Toxoid, killed Poliomylitis (Salk) Vaccine or attenuated organisms (BCG) Vaccine 2) Passive immunity- is attained by prepared antibodies and body cells do not take any active part in production of immunity  Natural passive immunity Example-transfer of antibodies of maternal origin transplacental IgG and Intestinal absorption from colostrums and milk  Artificial passive immunity By administration of Igs Homologous example –pooled human gamaglobulines used in treatment of measles, hypogamaglobulenemia, etc Heterologous example tetanus anti-toxin prepared in the horse Types of adaptive immunity: - There are two main types of adaptive immunity  Cell mediated immunity , which is responsible for defense against intracellular microbes & their toxins and mediated by T lymphocytes.  Humoral immunity which protects against extracellular microbes & their toxins and mediated by B lymphocytes & their secreted products, antibodies.  Tissues of the immune organs a)Central /primary immune organs - Are where immune cells are produced & mature. These are bone marrow & thymus b) Peripheral immune organs - Are where immune cells are presented with antigens and adaptive immune responses to microbes are intimated - These include lymph nodes, spleen, tonsils & extra-lymphatic organs such mucosal and cutaneous lymphoid tissue T lymphocytes - T lymphocytes are generated from immature precursors in the thymus - Mature, naïve T cells are found in the blood where they constitutes 60% to 70% of lymphocytes & in T cell zones of peripheral lymphoid organs such as lymph nodes & spleen - Each T cell is genetically programmed to recognize a specific cell-bound antigen by means of an antigen-specific T cell receptor (TCR) - CD4 & CD8 are expressed on two mutually exclusive subsets of T cells (CD4 T cells – 60% & CD8 T cells – 30% ) - T cells need two signals for activation Signal 1 –When TCR is engaged by the appropriate MHC bound antigen & the coreceptors CD4 & CD8 bind to MHC molecules Signal 2- The interaction of the CD28 molecule on T cells with the costimulatory molecules B7-1 & B7-2 expressed on antigen presenting cells CD4 T cells - They influence the function all other cells of the immune system - Two functionally distinct population of CD4 helper cells are recognized depending on different type of cytokines they produce  T-helper-1 (TH1) – synthesize IL-2 & interferon γ & are involved in delayed hypersensitivity, macrophage activation & production of antibodies such as Ig G  T-helper -2( TH2) – produce IL-4 or IL-5 or IL -13 & are involved in synthesis of Ig E & in activation of eosinophils CD8 + T cells Function mainly as cytotoxic cells to kill other cells B lymphocytes - B lymphocytes develop from immature precursors in the bone marrow. Mature B cells constitute 10% to 20% of the circulating peripheral lymphocyte population & are also present in peripheral lymphoid tissues such as lymph nodes , spleen or tonsils - B cells recognize antigen via B-cell antigen receptor complex. - Immunoglobulin M (IgM) & Ig D present on the surface of all naïve B cells, constitute the antigen- binding component of the B-cell receptor complex - B cell activation results in differentiation into antibody secreting cells , called plasma cells - Plasma cells produce different types of antibodies Macrophages - They play important role in induction & effector phase immune responses  Macrophages that have phagocytosed microbes & protein antigens process the antigens & present peptide fragments to T cells. Thus , macrophages are involved in the induction of cell mediated immune responses  Macrophages are activated by cytokines IFN-γ produced by T H1 cells. The activation enhances the microbicidal properties of macrophages & their ability to kill tumor cells  They are also important in the effector phase of humoral immunity. Macrophages phagocytose microbes that are opsonized by Ig G & C3b Dendritic cells - Dendritic cells are also another target cells for antigen presentation. These cells have numerous fine dendritic cytoplasmic processes - There are two types of dendritic cells  Mucosal dendrite cells (Langerhan’s cells). These cells capture antigens eg. a virus and it is transported to regional lymph nodes where the CD4 + T cells recognize it.  Follicular dendrite cells. These cells are found in germinal centers of lymphoid follicles in lymph nodes. 27  The induction & regulation of immune responses involve multiple interactions among lymphocytes, monocytes, inflammatory cells & endothelial cells. Such interactions depend on cell to cell contact & short acting soluble mediators. CYTOKINES - Cytokines are the messenger molecules of the immune system. 1)General functional categories Cytokines that mediate natural immunity IL-1, TNFα Cytokines that that regulate lymphocytes growth, activation and differentiation IL-2, IL-4, IL-5, IL-12, IL-15 Cytokines that activate inflammatory cells IFNδ, TNFα, TNF β Cytokines that affect leukocytes movements called chemokines C-C and C-X-C Cytokines that stimulate hemotopoisis Colony stimulating factor (CSF) from bone marrow General characteristics of cytokines -Many cytokines are pleiotropic i.e act on many cells & mediate many effects - Elaborate their effects on autocrine, paracrine and endocrine basis -Mediate their effects by binding to specific high affinity receptors Structure & function of histocompatibity molecules - Histocompatibilty molecules are important for the induction & regulation of the immune response - The principal physiologic function of the cell surface histocompatibility molecules is to bind peptide fragments of foreign proteins for presentation to antigen specific T cells - The genes encoding the most important histocompatibilty molecules are clustered on a small segment of chromosome 6, the major histocompatibilty complex(MHC) or the human leukocyte antigen (HLA) - The HLA system is highly polymorphic i.e there are many alleles of each MHC gene in the population & each individual inherits one (unique) set of these alleles.  On the basis of their chemical structure , tissue distribution & function, the MHC gene products are classified into three categories Class I & class II genes encode cell surface glycoproteins involved in antigen presentation Class III genes encode components of the complement system Class I MHC - These are expressed on all nucleated cells & platelets - They are encoded by three closely linked loci, designated HLA-A, HLA-B, & HLA-C - Class I MHC molecules bind & display peptides that are derived from proteins such as viral antigens, synthesized within the cell. - & present them to CD8+ cytotoxic T lymphocytes Class II MHC - These molecules are coded for in a region called HLA-D, which has three subregions: HLA-DP, HLA-DQ, & HLA-DR - The tissue distribution is restricted to antigen presenting cells (macrophages, dendritic cells) - Class II molecules present exogenous antigens(eg extracellular microbs) & recognized by CD4 T cells  Hypersensitivity reactions An exaggerated immune response that results in tissue injury. - Can be induced by exogenous environmental antigens or endogenous tissue antigens - Tissue injury in these reactions can be caused by humoral or cell mediated immune mechanisms. - There are four types of…. 1) Type I (anaphylactic or immediate type) reaction Can be defined as a rapidly developing immunologic reaction occurring, within minutes after the combination of an antigen with antibody bound to mast cells or basophiles in individuals previously sensitized to the antigen. Pathogenesis Presentation of the antigen (allergen) to precursor of TH2cells by antigen presenting dendritic cells on epithelial surfaces Newly minted TH2 cells produce clusters of cytokines including IL-3,IL-4,IL-5 and GM-CSF The IL-4 is essential for activation of B cells to produce IgE and IL-3 and IL-5 are important for the survival of eosinophilic activation  The IgE antibodies produced has a high affinity to attach to mast cells and basophiles A mast cell or basophil armed with cytophilic IgE antibodies is re-exposed to the specific allergen In this process multivalent antigens binds to more than one IgE molecules and cause cross-linkage with adjacent IgE antibody  This bridging of IgE molecules activates signal transduction pathways from cytoplasmic portion of IgE fc receptors. This signal initiates two parallel but independent processes. One leading to mast cell degranulation with discharge of preformed (primary) mediators and the other involving de novo synthesis and release of secondary mediators. (I)Mast cell degranulation discharge preformed granules such as primary mediators including biogenic amines, histamine, adenosine, eosinophlic and neutrophlic chemotactic factors, enzymes including proteases, and several acid hydrolases. (ii) The other involved is de novo synthesis and release of secondary mediators such as arachidomic metabolites - Leukotriens C4 & D4 – most potent vasoactive and spasmogenic agents known leukotriens B4– highly chemotatic for neutrophiles, eosinophiles and monocytes - Prostaglandin D2 – causes intense bronchospasm & increase mucus secretion - Platelet-activating factor release histamine, ↑ed vascular permeability - Cytokines—activation of inflammatory cells The two well-defined phases of type I hypersensitivity reactin are: a. Initial phase (response):Characterized by vasodilatation, vascular leakage, and depending on the location, smooth muscle spasm or glandular secretions. b. Late phase - As it is manifested for example in allergic rhinitis and bronchial asthma, more intense infiltration of eosinophiles, neutrophiles, basophilic, monocytes and CD4+ T cells are encountered and so does tissue destruction (epithelial mucosal cells). Systemic anaphylaxis - It is characterized by vascular shock, widespread edema & difficulty in breathing - It usually occurs after administration of foreign proteins, hormones, enzymes, polysacharides, & drugs. - Within minutes after exposure, itching, hives & skin erythema appear, followed shortly by contraction of respiratory bronchioles & respiratory distress. Laryngeal edema results in hoarsness. Vomiting, diarrhea & laryngeal obstruction follow. & the patient may go into shock & die. Local immediate hypersensitivity reactions - It is exemplified by atopic allergy. It involves localized reactions to common environmental allergens & is associated with familial predisposition - Specific diseases include allergic rhinitis (hay fever) & urticaria Type II hypersensitivity: It is mediated by antibodies directed toward antigens present on cell surfaces or extracellular matrix - The antigen may be intrinsic to the cell membrane or matrix or exogenous antigen  Three different antibody dependent mechanisms involved in this type of reaction (1) Opsonization & complement & Fc receptor mediated phagocytosis a)Direct lysis: It is effected by complements activation, formation of membrane attack complex (C5 – 9). This membrane attack complex then disrupts cell membrane integrity by drilling a hole. b) Opsoinization: By C3b, fragment of the complement to the cell surface enhances phagocytosis Examples include red blood cells, leukocytes and platelets disorders: Transfusion reaction; haemolytic anemia; Agranulocytosis; Thrombocytopenia; Certain drug reaction (2). Antibody dependent cell mediated cytotoxicity /ADCC/ - This type of antibody mediated cell injury does not involve fixation of complements. The target cells coated with IgG antibodies are killed by a variety of nonsensitized cells that have Fc receptors. The non-sensitized cells included in ADCC are monocytes/large granular/ lympholytes / Natural killer cells, neutrophils and eosinophils. -The cell lysis proceeds without phagocytosis. Example include graft rejection (3). Antibody mediated cellular dysfunction - In some cases, antibodies directed against cell surface receptors impair or dysregulate function without causing cell injury or inflammation. For example: In Myasthenia Gravis, antibodies reactive with acetylcholine receptors in the motor end plates of skeletal muscles impair neuromuscular transmission and cause muscle weakness. The converse is noted in Graves disease where antibodies against the thyroid-stimulating hormone receptor on thyroid epithelial cells stimulate the cells to produce more thyroid hormones. 3) Type III / Immune complex mediated - Type III hypersensitivity reaction is induced by antigen-antibody complex that produces tissue damage as a result of their capacity to activate the complement system. The antibodies involved in this reaction are IgG, IgM or IgA.  Two general types of antigens cause immune complex mediated injury  The antigen may be exogenous such as foreign protein, bacteria or virus  An endogenous antigen , it can be circulating antigen present in the blood or an antigen components of one’s cells & tissues  Pathogenesis of systemic immune complex disease has three phases a. Formation of Ag-Ab complex - Introduction of an antigen into the circulation, then production of specific antibodies by immuno- competent cells and subsequent antigen antibody formations b. Deposition of immune complexes - The mere formation of antigen-antibody complex in the circulation does not imply presence of disease. - Immune deposition depends on size of immune complexes & functional status of mononuclear phagocytic system - Sites of immune complex deposition include: Renal glomeruli, Joints, Skin, Heart, Serosal surfaces, Small blood vessels c. Inflammatory reaction - After immune complexes are deposited in tissues acute inflammatory reactions ensues and the damage is similar despite the nature and location of tissues. - Due to this inflammatory phase two mechanisms operate  Activation of complement cascades  Activation of neutrophils and macrophages through their Fc receptors Local immune complex disease (Arthus reaction) - The arthus reaction is a localized area of tissue necrosis resulting from acute immune complex vasculitis, usually elicited in the skin. Cell mediated (Type IV) hypersensitivity - The cell-mediated type of hypersensitivity is initiated by specifically sensitized T- lymphocytes. It includes the classic delayed type hypersensitivity reactions initiated by CD4+Tcell and direct cell cytotoxicity mediated by CD8+Tcell. - Typical variety of intracellular microbial agents including M. tuberculosis and so many viruses, fungi, as well as contact dermatitis and graft rejection are examples of type IV reactions 1. Delayed type hypersensitivity: this is typically seen in tuberculin reaction, which is produced by the intra- cutaneous injection of tuberculin, a protein lipopolysaccharide component of the tubercle bacilli. Steps involved in type lV reaction include  First the individual is exposed to an antigen for example to the tubercle bacilli where antigen presenting cells engulf the bacilli and present it to naïve CD4+ T-cells through MHC type ll antigens found on surfaces of antigen presenting cells (APC),  The initial macrophage (APC) and lymphocytes interactions result in differentiation of CD4+TH type cells. Some of these activated cells so formed enter into the circulation and remain in the memory pool of T cells for long period of time.  An intracutanous injection of the tuberculin for example to a person previously exposed individual to the tubercle bacilli , the memory TH1 cells interact with the antigen on the surface of APC and are activated with formation of granulomatous reactions T-CELL MEDIATED CYTOTOXICITY - In this variant of type IV reaction, sensitized CD8+T cells kill antigen-bearing cells. Such effector cells are called cytotoxic T lymphocytes (CTLs). -CTLs are directed against cell surface of MHC type l antigens and it plays an important role in graft rejection and in resistance to viral infections. It is believed that many tumor-associated antigens are effected by CTLs. Autoimmune diseases - Definition: Autoimmunity implies that an immune response has been generated against self-antigens /Autoantigens/. - Central to the concept of autoimmune diseases is a breakdown of the ability of the immune system to differentiate between self and non-self antigens. - To diagnose a disease as autoimmune , three requirement has to be met The presence of autoimmune reaction Evidence it is not secondary to tissue damage The absence of another well defined cause of disease - Autoimmune disease may result from IMMUNOLOGIC TOLERANCE -Immunologic tolerance is a state in which an individual is incapable of developing an immune response to specific antigens. - Self-tolerance refers to lack of responsiveness to an individual’s own antigens. Tolerance can be broadly classified in to two groups such as central and peripheral tolerance i) Central tolerance -This refers to clonal deletion where immature clones of T and B-lymphocytes that bear receptors for self- antigens are eliminated from the immune system during development in central lymphoid organs. T cells that bear receptors from self-antigens undergo apoptosis within/ during the process of T-cell maturation. ii) Peripheral tolerance 1. Clonal deletion by activation– induced cell death. The engagement of Fas by Fas ligand co-expressed on activated T-cells dampens the immune response by inducing apoptosis of activated T-cells ( Fas mediated apoptosis) 2. Clonal anergy Activaton of Ag specific T-cell requires two signals a). Recognition of peptide Ag with self-MHC molecules b). Co-stimulatory signals such as CD 28 must bind to their ligand called B7-1 and B7-2 on antigen presenting cells (APC) and if the Ag is presented by cell that do not bear CD28 ligand /i.e B7-1 or B7-2/ a negative signal is delivered and the cell becomes anergic (prolonged or irreversible functional inactivation of lymphocytes). c) Suppression by regulatory T cells D) Antigen sequestration some antigens are hidden from the immune system because the tissues in which these antigens are located don’t communicate with blood or lymph Eg brain, testis, eye (immune privileged sites) Mechanisms of autoimmune diseases  Most autoimmune diseases have genetic predisposition  Immunologic factors  Environmental triggers such as infection  Failure of peripheral tolerance: - Breakdown of T-cell anergy - T-cell anergy may be broken if the APC can be induced to express co-stimulatory molecules such as B7-1 and to secrete cytokines such as IL-12 that stimulate the generation of TH 1 cells. This up regulation of costimulator molecule B7-1 has been noted in multiple sclerosis, Rheumatoid arthritis, psoriasis and Insulin dependant diabetes mellitus (IDD). - Failure of activation induced cell death defects in Fas – Fas ligand System in generating apoptosis may allow persistence and proliferation of auto reactive T- cells in peripheral tissues. -Loss of regulatory or suppressor T- cells can limit the function of auto reactive T and B cells and thus, can lead to autoimmunity. Molecular mimicry (cross – reacting antigens). Some infections agents share epitopes with self-antigens. An immune response against such microbes may produce tissue-damaging reactions against the cross-reacting self- antigen. The classic example is streptococcal pharyngitis, in which antibodies are produced to the streptococcal M – protein and cross- react with M – protein of the sarcolemma of cardiac muscle to produce the acute rheumatic fever.  Polyclonal B-lymphocytic activation - Tolerance in some cases is maintained by clonal anergy. Autoimmunity may occur if such self – reactive but anergic clones are stimulated by antigen-independent mechanisms. Several micro-organisms and their products are capable of polyclonal (i.e antigen nonspecific) activation of B - cells. Examples include Epestein-barr virus (in infectious mononucleosis), gram-negative lipopolysaccharides (endotoxins). Release of sequestrated antigens - Any self-antigen that is completely sequestrated during development is likely to be viewed as foreign if introduced into the circulation, and an immune response develops.eg Agglutinating antibodies to spermatozoa may be produced following testicular trauma. Classification of autoimmune diseases  Organ specific autoimmune diseases affect a single organ or tissue including Hashimoto’s thyroiditis, Graves disease, Diabetes, chronic atropic gastritis, Myasthenia gravis Systemic or generalized autoimmune diseases affect many organs and tissues including Systemic lupus erythematosus Rheumatoid arthritis Systemic sclerosis Dermatomyositis Polymyositis Polyarteritis Nodosa Sjogren’s syndrome Prototype example of autoimmune disease Systemic lupus erythematosis (SLE) - Systemic lupus erythematosis is a classic prototype of non- organ specific autoimmune disease characterized by a bewildering array of autoantibodies particularly antinuclear antibodies (ANAS). It is a chronic remitting and relapsing often-febrile illness characterized principally by injury to the skin, joints, kidney and serosal membranes. Each and very part of the body may be affected. It is common among women of child bearing age and a female to male ratio of 9:1, pick on the 2nd to 4th decade Immunodeficiency diseases The term immunodeficiency covers a group of disorders of specific immune responses, neutrophil, macrophage and natural killer cells functions, as well as defects in the complement system that lead to impaired resistance to microbial infections. Immunodeficiency can be classified as Primary Secondary Primary immunodeficiency - Are exceedingly rare & almost always genetically determined - These disorders usually manifest in early childhood Primary immunodeficiency diseases are further divided into: Deficiencies of antibody (B – cells) immunity Eg. Infantile X-linked agammaglobinemia Deficiencies of cell mediated (T-cell) Immunity T-cell deficiencies are difficult to trace as T-cells affects B – cell functions Eg. Di George’s syndrome: Combined T-cell and B-cell deficiencies Eg Severe combined immunodeficiency disease (SCID) Secondary immunodeficiencies States These immunodeficiency states may be acquired secondary to various disease processes or drug effects  Protein deficiency  Hematologic malignancies  Acute viral infection  Chronic renal failure  Iatrogenic Steroids, cytotoxic drugs or radiotherapy for the treatment of malignancies.  Splenectomy  AIDS Acquired immunodeficiency syndrome AIDS is a retroviral disease characterized by profound immunosuppression that leads to opportunistic infections, secondary neoplasms and neurological manifestations. Mode of transmission - Transmission of HIV occurs under conditions that facilitate exchange of blood or body fluids containing the virus or virus infected cells Sexual activities 75% of all world-wide transmission is heterosexual transmission Viral transmission occurs in two ways  Direct inoculation into the blood vessels breached by trauma  Into dendritic cells or CD4+ cells within the mucosa Parenteral transmission Mother to child transmission - About 60% of this infection is transmitted during child- birth 25% during pregnancy and 15% during breast-feeding. Etiology - HIV is a non-transforming human retrovirus belonging to Lentivirus family. - Two type of HIV viruses HIV – 1 - USA, EUROPE, East & central Africa HIV - 2 - West Africa & India Structure of HIV - HIV-1 virion is spherical & contains an electron dense , cone shaped core surrounded by a lipid envelop derived from the host cell membrane The virus core contains  The major capsid protein p24 - It is the most readily detected viral antigen & is the target for the antibodies used for the diagnosis of HIV infection in ELISA  Nucleocapsid protein p7/p9  Two copies of genomic RNA  The three viral enzymes (protease, reverse transcriptase& integrase) - Studding the viral envelop are two viral glycoprotein , gp120 & gp41, which are important in HIV infection of cells - The HIV -1 RNA genome contains the gac, pol & env genes which code for different types of viral proteins - Considerable variability in certain parts of HIV genome is seen. Most variations are clustered in certain regions of the envelope glycoproteins - On the basis of genetic analysis, HIV-1 can be divided three subgroups, designated M(major), O (outlier) & N (neither M or O) - Group M viruses are the most common form & are further divided into several subtypes or clads, designated A through K. Pathogenesis of HIV infection & AIDS - Targets of HIV infections are:  The immune system and  Central nervous system - CD4 - Receptor molecule is a high affinity receptor for HIV - Target cells are those having CD4 receptors include CD4 + T helper cells Monocytes /macrophages Tissue cells such as dendritic cells present in genital tracts and anorectal region Certain brain cells (glial cells)  Initial binding of gp 120 to CD4 molecule leads to conformational change for the new recognition site on gp120 for the coreceptors, chemokine receptor CCR5 or CXCR4  The HIV strains can be classified into two groups based on their ability to infect macrophage and CD4 + T-cells. Macrophage tropic (M-tropic) stains can infect both monocytes/ macrophages and freshly isolated peripheral blood T-cells. T Tropic strains can infect only T cells both freshly isolated and retained in culture. M – tropic strains use CCR5 coreceptors whereas T – Tropic strains bind to CXCR4 coreceptors.  Ninty percent (90%) of HIV is transmitted by M – tropic strains, however over the course of infection. T – Tropic viruses gradually accumulate and these are virulent and cause final rapid phase of the disease progression  The second conformational change in gp41 results in insertion of a fusion peptide into the cell membrane of the target T-cells or macrophages. -After fusion, the viral core containing the HIV genome enters the cytoplasm of the cell (internalization). The life cycle of HIV virus after internalization, include DNA Synthesis- the uncoated viral RNA is copied into double stranded DNA by reverse transcriptase Viral integration-the DNA derived from the viruses in integrated into host genome by the viral integrate enzyme, thereby producing the latest proviral form of HIV-I. Viral replication- viral RNA is reproduced by transcriptional activation of the integrated HIV provirus  Viral dissemination- to complete the life cycle, viruses assembled in the cytoplasm and disseminate to other target cells after directly lysing the cell (direct cytopathic effect of the virus). - The HIV virus after internalization assumes two forms of infectivity such as latent infection and productive infections. In latent infections, the virus may be locked in the cytoplasm (preintegration latency) or after being integrated into host DNA (Post integration -The productive infection predominantly occur in lymphoid tissues, within macrophages, dendritic cells and CD4+T CELLS. Viremia after 8 weeks of infection supervene - Viremia is subsequently cleared by the development of an anti Viral immune response effected by CD8+cytotoxic T cells - This results in transient decrease in CD4+T cells and an apparent rise in CD8+T cells - As viremia declines, the HIV disseminates into lymphoid tissues and undergoes clinical latency but not viral latency - The decline in CD4 T cells with variable time results in AIDS. HIV infection of non T cells - HIV infection of macrophages has three implications  They represent a veritable virus factory & reservior  Macrophage provide a safe vehicle for HIV to be transported to various parts of the body including the nervous system  In late stage of HIV infection when CD4+ T cells are depleted, they may be an important site for continued viral replication - Dendritic cells are also important targets for initiation & maintenance HIV infection  Mcosal dendritic cells are infected by the virus & transport it to regional lymph nodes  Follicular dendritic cells similar to macrophages are reservoirs of HIV B cells - Patients with AIDS show profound abnormality in B cell function Hypergammaglobulinemia & Polyclonal B cell activation Inability to mount antibody response to new antigens - CD4+ T cells, macrophages & follicular dendritic cells contained in the lymphoid tissue are the major sites of HIV infection & persistence Pathogenesis of central nervous system involvement - The nervous system is major target of HIV infection - Macrophages & microglia are the predominant cell types in the brain that are infected with HIV - It is believed HIV is carried to the brain by infected monocytes - The neurologic deficit is assumed to be caused indirectly by viral products & by soluble factors produced by infected microglia Natural history of HIV infection -Three phases reflecting the dynamics of virus - host interaction are recognized Early acute phase: - Acute retroviral syndrome represents the initial or primary response of an immunocompetent adult to HIV infection - It is characterized by high level of viral production, viremia and widespread seeding of lymphoid tissues. - Its spread is controlled by immune system and the virus is mainly swept into the lymph nodes. - The decline in HIV viral load usually coincides with the time of sero-conversion and the primary or early HIV infection. Acute phase occurs 4 – 8 weeks after acquiring the virus. There may be a short (1 – 2 weeks) seroconversion illness which cause the following in about 50-70% individuals: fever, rash sore throat, muscle and joint pain and some lymph node swelling. - The level of viral load in early acute phase of the disease is called the set point and anti retroviral therapy can reduce this set point thus, early detection especially in cases of needle stick injuries, rape and other known risky exercises can benefit from it The middle chronic phase Relative containment of the viruses with a period of clinical latency (not viral latency). Patients may be asymptomatic or develop persistent generalized lymphadenopathy (PGL) and PGL is defined as palpable lymphadenopathy at two or more extra – inguinal sites, persisting for more than 3 months in persons infected with HIV. Minor opportunistic infections such as trush, herpes zoster etc may occur The final crisis phase (AIDS) - It is characterized by a breakdown of host defense, a dramatic increase in plasma virus& clinical disease - Typically the patient presents with Prolonged fever > 1/12 Fatigue, weight loss and diarrhea CD4 + T cells < 500 /μl - HIV infection in absence of treatment progress to AIDS within 7 to 10 years in most cases, however exceptions to this typical course also occur Long term non progressors- untreated HIV-1 individuals who remain asymptomatic for 10 years or more with stable CD4 +T-cells count and low plasma viremia Rapid Progressors - Groups of patients with the middle chronic phase is telescoped to 2-3 years after primary infection Clinical features of AIDS - The typical adult patient with AIDS presents with fever, weight loss, diarrhea, generalized lymphadenopathy, multiple opportunstic infection, neurologic diseases & secondary neoplasms  P.carnii pneumonia - Represents reactivation of latent infection - The risk of developing this infection is high in individuals with fewer than 200 CD4+ T cells/μL - Candidiasis is the most common fungal infection in patients with AIDS. Infection of oral cavity & esophagus are the most common clinical manifestation - Cytomegalovirus may cause disseminated disease but most commonly it affects eye & gastrointestinal tract - Disseminated infection with atypical mycobacteria (mainly M. avium- intracellulare) occurs late  Cryptococcosis occurs in 10% of AIDS patients Meningitis is the major clinical manifestation - Toxoplasma gondii is a protozoan parasite that most often leads to infection of the brain with AIDS. The lesions are usually multiple and have the appearance of abscesses. Less commonly, T gondii infection is disseminated to other organs.  Persistent diarrhea in AIDS is caused by infections with protozoan such as cryptosporidium, isospora belli or microsporidia  Secondary neoplasms Kaposi sarcoma – composed of mesenchymal (spindle) cells that form blood vessels. It is strongly linked to infection of KS-associated herpesvirus (HHV-8) CNS manifestations - Opportunistic infections & neoplasms - Self limited meningoencephalitis occuring during seroconversion - Peripheral neuropathy - Vacuolar myelopathy - AIDS dementia complex Other tumors - AIDS related lymphoma - Cervical carcinoma - Anal cancer