1. Dr Rehma Dar Assistant professor Pathology

2.  Introduction to Immune System  Cell mediated vs Humoral Immunity  Hypersensitivity reactions  Autoimmune diseases  Transplant Rejection  Immunodeficiency states

3. The immune system is vital for survival- protects us from infectious pathogens.

4. The mechanisms of protection against infections fall into two broad categories.  Innate immunity  Adaptive immunity

6.  natural, or native immunity refers to defense mechanisms - present even before infection and protect individuals against infections.  first line of defense, because it is always ready to prevent and eradicate infections.

7.  epithelial barriers,  phagocytic cells (mainly neutrophils and macrophages), dendritic cells, natural killer (NK) cells, and  several plasma proteins, including complement system.

8. The two most important cellular reactions of innate immunity are:  inflammation, in which phagocytic leukocytes are recruited and activated to kill microbes, and  anti-viral defense, via dendritic cells and NK cells.

9.  Leukocytes and epithelial cells recognize components of microbes (called pathogen associated molecular patterns) via cellular receptors.  The recognition receptors are a family of proteins called Toll-like receptors (TLRs) that are homologous to the Drosophila protein Toll.  Different TLRs are specific for components of different bacteria and viruses.  TLRs are located on the cell surface and in endosomes-recognize and initiate cellular responses to extracellular and ingested microbes.

10.  Other microbial sensors are located in the cytoplasm -recognize bacteria and viruses that may have colonized cells.  Upon recognition of microbes, the TLRs and other sensors signal by a common pathway - the activation of transcription factors, NF-κB (nuclear factor κB).  NF-κB turns on the production of cytokines and proteins that stimulate the microbicidal activities of phagocytes.

11.  Epithelia of the skin and GITand respiratory tracts - mechanical barriers to the entry of microbes  also produce anti-microbial molecules such as defensins, and lymphocytes located in the epithelia combat microbes at these sites.  Monocytes and neutrophils –phagocytes -rapidly be recruited to any site of infection  Dendritic cells produce type I interferons, anti-viral cytokines that inhibit viral infection and replication  Natural killer cells - protection against many viruses and intracellular bacteria

12.  Complement system is activated by microbes using the alternative and lectin pathways; in adaptive immunity it is activated by antibodies using the classical pathway.  Other proteins of innate immunity are mannose- binding lectin and C-reactive protein - coat microbes for phagocytosis.  Lung surfactant - provide protection against inhaled microbes.

13.  Acquired or specific immunity consists of mechanisms that are stimulated by (“adapt to”) microbes and are capable of recognizing microbial and nonmicrobial substances.  develops later, and is even more powerful than innate immunity in combating infections.  By convention, the term “immune response” refers to adaptive immunity

14.  The adaptive immune system consists of lymphocytes and their products, including antibodies.  The receptors of lymphocytes are much more diverse - not inherently specific for microbes, and they are capable of recognizing a vast array of foreign substances.

15. There are two types of adaptive immunity:  Humoral immunity  Cell-mediated immunity

16.  Humoral immunity - protects against extracellular microbes and their toxins,  mediated by B (bone marrow–derived) lymphocytes and their secreted products, antibodies (also called immunoglobulins, Ig)  Cell-mediated immunity- responsible for defense against intracellular microbes,  mediated by T (thymus-derived) lymphocytes.  Both classes of lymphocytes express highly specific receptors for a wide variety of substances, called antigens.

18.  appear morphologically similar – heterogeneous  Mature lymphocytes that have not encountered specific antigen - naive (immunologically inexperienced).  activated by recognition of antigens - differentiate into effector cells, which perform the function of eliminating microbes, and  memory cells, better able to combat the microbe in case it returns

19.  T Lymphocytes  B Lymphocytes  NK cells

20.  develop from precursors in the thymus.  constitute 60% to 70% of blood lymphocytes and in T-cell zones of peripheral lymphoid organs (paracortical & medullary)  Each T cell recognizes a specific cell-bound antigen by means of an antigen-specific T-cell receptor (TCR).

22.  TCR recognizes peptide antigens that are displayed by major histocompatibility complex (MHC) molecules on the surfaces of antigen-presenting cells (APCs).  CD4+ T cells (Helper) :60% of T lymphocytes  CD8+ T cells (Cytotoxic): 30% of T lymphocytes  Normal 2:1 (CD4+ : CD8+)

24.  TCR disulfide-linked α and a β polypeptide chain having a variable (antigen-binding) region and a constant region.  TCR diversity - somatic rearrangement of the genes that encode the TCR α and β chains  Each TCR linked to CD3 complex -transduction of signals into the T cell after the TCR has bound the antigen  T cells express CD4, CD8, CD2, integrins, and CD28 -assist the functional responses.

25.  develop from precursors in the bone marrow.  constitute 10% to 20% of the circulating lymphocyte and also present in peripheral lymphoid tissues like lymph nodes(germinal centers), spleen, and mucosa-associated lymphoid tissues.  recognize antigen via the B-cell antigen receptor complex.

26.  Membrane-bound antibodies called IgM and IgD, present on the surface of all mature, naive B cells, are the antigen-binding component of the B-cell receptor complex  After stimulation - B cells - plasma cells that secrete antibodies, the mediators of humoral immunity.  B cells also express complement receptors, Fc receptors, and CD40- essential for their responses.

28.  10% to 15% of peripheral blood lymphocytes.  do not express TCRs or Ig.  contain abundant azurophilic granules; because of these characteristics, they are also called large granular lymphocytes.  early line of defense against viral infections and some tumors  Neither prior sensitization nor Ab is involved in killing  secrete cytokines, such as interferon-γ (IFN- activates macrophages to destroy ingested microbes- intracellular microbial infections.

30.  numerous fine cytoplasmic processes that resemble dendrites  the most important antigen-presenting cells (APCs) for initiating primary T-cell responses  Located under epithelia, the common site of entry of microbes and foreign antigens, and in the interstitia of all tissues, where antigens may be produced.  Immature dendritic cells within the epidermis are called Langerhans cells.  express many receptors for capturing and responding to microbes

32.  part of the mononuclear phagocyte  phagocytosed microbes and protein antigens process the antigens and present peptide fragments to T cells. - function as APCs in T-cell activation.( MHC II to CD4+)  key effector cells in certain forms of cell-mediated immunity, the reaction that serves to eliminate intracellular microbes.  also participate in the effector phase of humoral immunity-phagocytose and destroy microbes opsonized (coated) by IgG or C3b.

33.  Generative Lymphoid Organs also called primary, or central  Peripheral Lymphoid Organs or secondary

34. Generative Lymphoid Organs  in which T and B lymphocytes mature and become competent to respond to antigens  thymus, where T cells develop, and the bone marrow, where B lymphocytes mature. Peripheral Lymphoid Organs  in which adaptive immune responses to microbes are initiated.  lymph nodes, spleen, and the mucosal and cutaneous lymphoid tissues.

35.  HLA system – group of related proteins called as HLA antigens.  Genes that code for HLA are called histocompatibility genes.  responsible for tissue compatibility between individuals.  The physiologic function of MHC molecules is to display peptide fragments of proteins for recognition by antigen-specific T cells

36.  genes encoding the major histocompatibility molecules are clustered on a small segment of chromosome 6, the major histocompatibility complex, or the human leukocyte antigen (HLA) complex

40.  fundamental to the recognition of antigens by T cells and are linked to many autoimmune diseases  evoke rejection of transplanted organs,  are responsible for tissue compatibility between individuals.  highly polymorphic, - many alleles of each MHC gene in the population and each individual inherits one set of these alleles that is different from the alleles in most other individuals.

41.  On the basis of their structure, cellular distribution, and function, MHC gene products are classified into three groups.  Class I MHC molecules are expressed on all nucleated cells and platelets except RBC  They are encoded by three closely linked loci, designated HLA-A, HLA-B, and HLA-C

42.  Since CD8+ T cells recognize peptides only if presented as a complex with self–class I MHC molecules, CD8+ T cells are said to be class I MHC– restricted.  Because one of the important functions of CD8+ CTLs is to eliminate viruses, which may infect any nucleated cell- nucleated cells express class I HLA molecules and can be surveyed by CD8+ T cells.

43.  Class II MHC molecules are encoded in a region called HLA-D, which has three subregions: HLA- DP, HLA-DQ, and HLA-DR.  The class II - binding site for CD4, and, the class II–peptide complex is recognized by CD4+ T cells, which function as helper cells- they are referred to as class II MHC–restricted.  mainly expressed on cells that present ingested antigens and respond to T-cell help (macrophages, B lymphocytes, and dendritic cells).

44.  Class III MHC molecules - MHC locus also contains genes - encode some complement components and the cytokines tumor necrosis factor (TNF) and lymphotoxin  contains genes that encode many proteins involved in antigen processing and presentation

46. Antigen processing and display by major histocompatibility complex (MHC) molecules

47.  MHC molecules play key roles in regulating T cell– mediated immune responses  MHC molecules ensure that the correct immune response is mounted against different microbes—  CD8+ T against cytoplasmic microbes, and  antibodies and macrophages (both of which are activated by CD4+helper T cells) against extracellular microbes.

48.  A variety of diseases are associated with the inheritance of certain HLA alleles  The most striking is the association between ankylosing spondylitis and HLA-B27;  individuals who inherit this class I HLA allele have a 90-fold greater chance (relative risk) of developing the disease as compared with those who do not carry HLA-B27.

49.  The diseases that show association with the HLA locus can be broadly grouped into the following categories:  1. Inflammatory diseases, including ankylosing spondylitis and several post-infectious arthropathies, all associated with HLA-B27  2. Autoimmune diseases, including autoimmune endocrinopathies, associated mainly with alleles at the DR locus  3. Inherited errors of metabolism, such as 21- hydroxylase deficiency (HLA-BW47) and hereditary hemochromatosis (HLA-A)

51.  The induction and regulation of immune responses involve multiple interactions among lymphocytes, dendritic cells, macrophages, other inflammatory cells (e.g., neutrophils), and endothelial cells  mediated by short-acting secreted mediators called cytokines

52.  Cytokines of innate immunity produced by macrophages, dendritic cells, and NK cells, and mediate inflammation and anti-viral defense; these include TNF, IL-1, IL-12, type I IFNs, IFN-γ, and chemokines  Cytokines of adaptive immune responses are made principally by CD4+ T lymphocytes - promote lymphocyte proliferation and differentiation and to activate effector cells. The main ones in this group are IL-2, IL-4, IL-5, IL-17, and IFN-γ

53.  Activation of T Lymphocytes and Elimination of Intracellular Microbes  Naive T lymphocytes are activated by antigen  proliferate and differentiate into effector cells that migrate to any site where the antigen (microbe) is present  CD4+ helper T cells - cytokine IL-2 and expression of high-affinity receptors for IL-2.  Activated CD8+ lymphocytes differentiate into CTLs - kill cells harboring microbes in the cytoplasm.

56.  Activation of B Lymphocytes and Elimination of Extracellular Microbes  Upon activation, B lymphocytes proliferate  and then differentiate into plasma cells that secrete different classes of antibodies with distinct functions  Cytokines that stimulate the production of antibodies with high affinities for the antigen. This process, called affinity maturation,

57. The humoral immune response combats microbes in many ways  Antibodies bind to microbes and prevent them from infecting cells, thus “neutralizing” the microbes.  IgG antibodies coat (“opsonize”) microbes and target them for phagocytosis, since phagocytes (neutrophils and macrophages) express receptors for the Fc tails of IgG.  IgG and IgM activate the complement system by the classical pathway- phagocytosis and destruction of microbes.

58.  Some antibodies serve special roles at particular anatomic sites. IgA -mucosal epithelia and neutralizes microbes in the lumens of the respiratory and gastrointestinal tracts  IgG is actively transported across the placenta and protects the newborn until the immune system becomes mature.  IgE and eosinophils cooperate to kill parasites  IgG antibodies have half-lives of about 3 weeks.  Some plasma cells migrate to the bone marrow - continuing to produce low levels of antibodies.

60.  effector lymphocytes induced by an infectious pathogen die by apoptosis after the microbe is eliminated, - immune system to its basal resting state, called homeostasis.  The activation of lymphocytes also generates long- lived memory cells  Memory cells - antigen-specific lymphocytes (more numerous than the naive cells specific for any antigen that are present before),  respond faster and more effectively when re- exposed to the antigen than do naive cells- generation of memory cells is an important goal of vaccination.

63.  Individuals who have been previously exposed to an antigen are said to be sensitized.  repeat exposures to the same antigen trigger a pathologic reaction; -hypersensitivity, - excessive response to antigen.  Both exogenous and endogenous antigens may elicit hypersensitivity reactions.

64.  Exogenous antigens include those in dust, pollens, foods, drugs, microbes, chemicals, blood products that are used in clinical practice.  The immune responses ranging from annoying discomforts, such as itching of the skin, to potentially fatal diseases, such as bronchial asthma and anaphylaxis

65.  Injurious immune reactions -evoked by endogenous tissue antigens.  Immune responses against self-, cause the autoimmune diseases.  hypersensitivity diseases - associated with the inheritance of particular susceptibility genes( HLA genes and many non-HLA genes)

66.  Hypersensitivity diseases -associated with the inheritance of susceptibility genes(HLA genes and many non-HLA genes)  imbalance between the effector and the control mechanisms of immune responses

67. classified on the basis of the immunologic mechanism that mediates the disease  In immediate hypersensitivity (type I hypersensitivity), mediated by T H 2 cells, IgE antibodies, and mast cells-release of mediators that act on vessels and smooth muscle and of pro- inflammatory cytokines that recruit inflammatory cells.

70.  rapid immunologic reaction occurring within minutes after the combination of an antigen with antibody bound to mast cells in individuals previously sensitized to the antigen.  These reactions are often called allergy, and the antigens that elicit them are allergens.

72.  Immediate hypersensitivity may occur as a systemic or local reaction.  The systemic reaction usually follows injection of an antigen into a sensitized individual.  Sometimes, within minutes the patient goes into a state of shock, which may be fatal.

73.  Local reactions are diverse and vary depending on the portal of entry of the allergen.  localized cutaneous swellings (skin allergy, hives), nasal and conjunctival discharge (allergic rhinitis and conjunctivitis), hay fever, bronchial asthma, or allergic gastroenteritis (food allergy).

80.  Many local type I hypersensitivity reactions have two well-defined phases  The immediate or initial reaction characterized by vasodilation, vascular leakage, and depending on the location, smooth muscle spasm or glandular secretions.  evident within 5 to 30 minutes after exposure to an allergen and tend to subside in 60 minutes.

81.  a second, late-phase reaction sets in 2 to 24 hours later without additional exposure to antigen and may last for several days.  This late-phase reaction is characterized by infiltration of tissues with eosinophils, neutrophils, basophils, monocytes, and CD4+ T cells as well as tissue destruction, typically in the form of mucosal epithelial cell damage.

84.  T H 2 cells play a central role in the initiation and propagation of - by stimulating IgE production and promoting inflammation.  The first step is the presentation of the antigen to naive CD4+ helper T cells, by dendritic cells - cytokines such as IL-4 - T cells differentiate into T H 2 cells.  T H 2 cells produce a cytokines IL-4, IL-5, and IL-13. IL-4 acts on B cells to stimulate class switching to IgE,  Mast cells and basophils express a high-affinity receptor, called FcεRI- specific for the Fc portion of IgE

85.  The bridging of the Fcε receptors -signal transduction - mast cell degranulation with the discharge of preformed (primary) mediators and de novo synthesis and release of secondary mediators, including lipid products and cytokines -mediators responsible for the clinical expression of immediate hypersensitivity reactions.

88.  Mast cells are bone marrow–derived cells that are widely distributed in the tissues.  abundant near blood vessels and nerves and in subepithelial tissues, -  why local immediate hypersensitivity reactions often occur at these sites.  Mast cells have cytoplasmic membrane- bound granules that contain a variety of biologically active mediators.

89.  Basophils are similar to mast cells in many respects, including the presence of cell surface IgE Fc receptors as well as cytoplasmic granules.  But not normally present in tissues but rather circulate in the blood in extremely small numbers. - basophils can be recruited to inflammatory sites.

90. Vasoactive amines. Histamine- causes intense smooth muscle contraction, increased vascular permeability, and increased mucus secretion by nasal, bronchial, and gastric glands. Enzymes. include neutral proteases (chymase, tryptase) and several acid hydrolases. - tissue damage and lead to the generation of kinins and activated components of complement (e.g., C3a) Proteoglycans. include heparin, and chondroitin sulfate- pack and store the amines in the granules.

91.  Synthesized in the mast cell membranes that lead to activation of phospholipase A 2- acts on membrane phospholipids to yield arachidonic acid.  leukotrienes and prostaglandins are derived by the 5-lipoxygenase and cyclooxygenase pathways  Leukotrienes. Leukotrienes C 4 and D.  Prostaglandin D 2. (cyclooxygenase pathway)  Platelet-activating factor - production of PAF is also triggered by the activation of phospholipase A 2, - not a product of arachidonic acid metabolism.

92.  TNF, IL-1, and chemokines, - promote leukocyte recruitment (typical of the late- phase reaction);  IL-4, which amplifies the T H 2 response; and numerous others.

95. Edematous - Swollen, Fluid-Influx "Wheal" Erythrematous - Reddened, Vasodilated, Blood-cell Influx "Flare" Manifestation of Type I Hypersensitivity in Skin: "Hives"

97.  genetically determined.  atopy refers to a predisposition to develop localized immediate hypersensitivity reactions to a variety of inhaled and ingested allergens  higher serum IgE levels, and more IL-4–producing T H 2 cells  triggered by temperature extremes and exercise, and do not involve T H 2 cells or IgE; such reactions are sometimes called “non-atopic allergy.”

98.  characterized by vascular shock, widespread edema, and difficulty in breathing.  It may occur in sensitized individuals after administration of foreign proteins (e.g., antisera), hormones, enzymes, polysaccharides, and drugs (such as the antibiotic penicillin), exposure to food allergens (e.g. peanuts, shellfish) or insect toxins.

99.  (type I) hypersensitivity is a complex disorder -IgE-mediated - mast cells and inflammatory cells cells (particularly eosinophils), - T H 2 helper T - release of mast cell mediators and eosinophil-rich inflammation.

100.  In antibody-mediated disorders (type II hypersensitivity), secreted IgG and IgM antibodies participate directly in injury to cells by - phagocytosis or lysis and injury to tissues  Antibodies may also interfere with cellular functions and cause disease without tissue injury.

101.  that react with antigens present on cell surfaces or in the extracellular matrix.  The antigenic determinants may be intrinsic to the cell membrane or matrix or  exogenous antigen, such as a drug metabolite, that is adsorbed on a cell surface or matrix.  In either case the hypersensitivity reaction results from the binding of antibodies to normal or altered cell surface antigens

102. The antibody-dependent mechanisms that cause tissue injury and disease

104.  Cells opsonized by IgG antibodies are recognized by phagocyte Fc receptors  activate the complement system by the classical pathway -generates by-products, mainly C3b and C4b, deposited on the surfaces of the cells and recognized by phagocytes

105.  Antibody-mediated destruction of cells by another process called antibody-dependent cellular cytotoxicity (ADCC)  Cells coated with low concentrations of IgG antibody are killed by effector cells,  bind to the target cells by their receptors for the Fc fragment of IgG- cell lysis  mediated by monocytes, neutrophils, eosinophils, and NK cells.

107.  Transfusion reactions  Hemolytic disease of the newborn (erythroblastosis fetalis)  Autoimmune hemolytic anemia, agranulocytosis, and thrombocytopenia  certain drug reactions, in which a drug acts as a “hapten” by attaching to surface molecules of red cells and antibodies -against the drug–membrane protein complex.

108. Transfusion reactions Produced by mismatched blood types Destroys foreign RBC by complement-mediated lysis triggered by IgG Produces fever, intravascular clots, lower back pain, Hgb in urine Free Hgb produced has 2 fates: passes to the kidneys – hemoglobinuria Breaks down to bilirubin..can be toxic

110.  When antibodies deposit in fixed tissues, such as basement membranes and extracellular matrix  antibodies activate complement, generating chemotactic agents (C5a), - migration of polymorphonuclear leukocytes and monocytes, and anaphylatoxins (C3a and C5a), - increase vascular permeability  The leukocytes - release or generation of a variety of pro-inflammatory substances- prostaglandins, and chemotactic substances.

111.  Leukocyte activation - substances that damage tissues, such as lysosomal enzymes, including proteases capable of digesting basement membrane, collagen, elastin, and cartilage, and reactive oxygen species EXAMPLES  some forms of glomerulonephritis, vascular rejection in organ grafts

112.  antibodies directed against cell surface receptors impair or dysregulate function without causing cell injury or inflammation Example  in myasthenia gravis, antibodies - acetylcholine receptors in the motor end plates of skeletal muscles block neuromuscular transmission -cause muscle weakness.

113.  antibody-mediated stimulation of cell function) - Graves disease.  antibodies against the thyroid stimulating hormone(TSH) receptor on thyroid epithelial cells stimulate the cells, resulting in hyperthyroidism

115.  Immune complex–mediated disorders (type III hypersensitivity), IgG and IgM antibodies bind antigens usually in the circulation, and  the antigen-antibody complexes deposit in tissues and induce inflammation- tissue damage by inflammatory cells  within the circulation (circulating immune complexes), and deposited typically in vessel walls  Sometimes at extravascular sites where antigen may have been “planted

116.  The antigens may be exogenous, such as a foreign protein that is injected or produced by an infectious microbe, or  endogenous, if the individual produces antibody against self-components (autoimmunity).

117.  Diseases can be systemic, if immune complexes are formed in the circulation and are deposited in many organs, or  localized to particular organs, such as the kidney (glomerulonephritis), joints (arthritis), or the small blood vessels of the skin if the complexes are deposited or formed in these tissues

119.  Acute serum sickness - sequela to the administration of large amounts of foreign serum (e.g., serum from immunized horses used for protection against diphtheria.

120. The pathogenesis of systemic immune complex disease can be divided into three phases:  (1) formation of antigen-antibody complexes in the circulation;  (2) deposition of the immune complexes in various tissues, thus initiating  (3) an inflammatory reaction at the sites of immune complex deposition

122.  Antigen - antibodies, typically about a week after the injection of the protein. These antibodies are secreted into the blood, where they react with the antigen still present in the circulation and form antigen-antibody complexes.

123.  circulating antigen-antibody complexes are deposited in various tissues.  In general, complexes that are of medium size, are the most pathogenic.  Organs where blood is filtered at high pressure, like urine and synovial fluid, are favored; hence, immune complexes frequently deposit in glomeruli and joints

124.  Once deposited in the tissues - acute inflammatory reaction  During this phase (approximately 10 days after antigen administration), clinical features such as fever, urticaria, joint pains (arthralgias), lymph node enlargement, and proteinuria appear.  Vasculitis - blood vessels, glomerulonephritis - renal glomeruli, arthritis -joints  It is clear that complement-fixing antibodies (i.e., IgG and IgM induce the pathologic lesions of immune complex disorders.

125. Immune complex vasculitis. The necrotic vessel wall is replaced by smudgy, pink “fibrinoid” material.

126.  localized area of tissue necrosis resulting from acute immune complex vasculitis, usually elicited in the skin.  intracutaneous injection of antigen in a previously immunized animal that contains circulating antibodies against the antigen- and large immune complexes are formed locally.  These complexes precipitate in the vessel walls and cause fibrinoid necrosis, and superimposed thrombosis worsens the ischemic injury.

128.  antigen-activated (sensitized) T lymphocytes, including CD4+ and CD8+ T cells (T H 1 and T H 17 cells and CTLs)  Cause cellular and tissue injury

129.  CD4+ T cell–mediated hypersensitivity induced by environmental and self-antigens - chronic inflammatory disease.  Many autoimmune diseases - inflammatory reactions by CD4+ T cells  some of T cell–mediated autoimmune diseases, CD8+ cells may also be involved.  In viral infections, CD8+ cells may be the dominant effector cells.

131. Mechanisms of T cell–mediated (type IV) hypersensitivity reactions

132.  exogenously administered antigens  chronic inflammatory reactions against self- tissues.  Both T H 1 and T H 17 cells  The inflammatory reaction associated with T H 1 cells is dominated by activated macrophages,  and that triggered by T H 17 cells has a greater neutrophil component.

133.  The cellular events in T cell–mediated hypersensitivity consist of a series of reactions - cytokines play important roles. The reactions can be divided into the following stages.  Proliferation and Differentiation of CD4+ T Cells.  Responses of Differentiated Effector T Cells.

134.  CD4+ T cells recognize peptides displayed by dendritic cells - IL-2- autocrine growth factor to stimulate proliferation of the antigen-responsive T cells.  The differentiation of antigen-stimulated T cells to T H 1 or T H 17 cells - cytokines produced by APCs (dendritic cells and macrophages) at the time of T- cell activation  IFN-γ by these effector cells - T H 1 development- amplifying the reaction.  IL-1, IL-6, and IL-12, IL-23, TGF-β (made by many cell - differentiation of T cells to the T H 17 subset.

135.  Some of the differentiated effector cells enter the circulation remain in the memory pool of T cells for long periods

136.  Upon repeat exposure previously activated T cells recognize to an antigen  T H 1 cells IFN-γ, - manifestations of delayed-type hypersensitivity.  IFN-γ–activated macrophages are altered in several ways:  their ability to phagocytose and kill microorganisms  express more class II MHC - antigen presentation  TNF, IL-1, and chemokines- inflammation  Produce IL-12- amplifying the T H 1 response.

137.  Thus, activated macrophages serve to eliminate the offending antigen; if the activation is sustained- tissue injury result.

138.  T H 17 cells activated by e microbial antigens and by self-antigens in autoimmune diseases.  secrete IL-17, IL-22, chemokines- recruit neutrophils and monocytes to the reaction, - inflammation.  IL-21, which amplifies the T H 17 response.

139.  The classic example of DTH is the tuberculin reaction,  intracutaneous injection of purified protein derivative (PPD, also called tuberculin), a protein- containing antigen of the tubercle bacillus.  In a previously sensitized individual, reddening and induration of the site appear in 8 to 12 hours, reach a peak in 24 to 72 hours, and thereafter slowly subside.

142.  the accumulation of mononuclear cells, mainly CD4+ T cells and macrophages, around venules, producing perivascular “cuffing”  venules show marked endothelial hypertrophy, cytokine-mediated endothelial activation

143.  With certain persistent or nondegradable antigens, such as tubercle bacilli colonizing the lungs or other tissues, infiltrate is dominated by macrophages over a period of 2 or 3 weeks.  The activated macrophages - morphologic transformation into - epithelioid cells.  A microscopic aggregation of epithelioid cells, usually surrounded by a collar of lymphocytes, is referred to as a granuloma  This pattern called granulomatous inflammation

145.  Contact dermatitis is a common example of tissue injury resulting from DTH reactions.  It may be evoked by contact with urushiol, the antigenic component of poison ivy or poison oak- vesicular dermatitis

148.  CD8+ CTLs kill antigen-bearing target cells.  Tissue destruction by CTLs - type 1 diabetes.  CTLs directed against cell surface histocompatibility - graft rejection  virus-infected cell, viral peptides displayed by class I MHC molecules - TCR of CD8+ T lymphocytes- killing of infected cells, cell damage (e.g., in viral hepatitis).  Tumor-associated antigens are also presented on the cell surface- tumor rejection

149.  The T cell–mediated killing of targets involves perforins and granzymes- preformed mediators contained in granules of CTLs  Granzymes are proteases that cleave and activate caspases, - apoptosis of the target cells  CD8+ T cells also produce IFN-γ - iinflammatory reactions following virus infections and exposure to some contact sensitizing agents.

151. Type I IgE Mediated Classic Allergy Type II IgG/IgM Mediated rbc lysis Type III IgG Mediated Immune complex Disease Type IV T cell Delayed Type Hypersensitivity

152.  Immune reactions against self-antigens— autoimmunity—  1% to 2% of the US population.  Autoantibodies can be found in the serum of apparently normal individuals, particularly in older age groups  autoantibodies are also formed after damage to tissue – serve to remove tissue breakdown products.

153.  Also called as immune-mediated inflammatory diseases - uncertainty about the target antigens  contribution of chronic inflammation to the pathogenesis of these diseases.

154. Criteria :  (1) the presence of an immune reaction specific for some self-antigen or self-tissue;  (2) evidence that such a reaction is not secondary to tissue damage but is of primary pathogenic significance; and  (3) the absence of another well-defined cause of the disease

155. DISEASES MEDIATED BY ANTIBODIES AND IMMUNE COMPLEXES Organ-specific autoimmune diseases Autoimmune hemolytic anemia Myasthenia gravis Graves disease Goodpasture syndrome Systemic autoimmune diseases Systemic lupus erythematosus (SLE) Diseases caused by autoimmunity or by reactions to microbial antigens Polyarteritis nodosa Immune-Mediated Inflammatory Diseases

156. DISEASES MEDIATED BY T CELLS Organ-specific autoimmune diseases Type 1 diabetes mellitus Multiple sclerosis Systemic autoimmune diseases Rheumatoid arthritis Systemic sclerosis Sjogren syndrome Diseases caused by autoimmunity or by reactions to microbial antigens Inflammatory bowel disease (Crohn disease, ulcerative colitis) Inflammatory myopathies

157. The systemic diseases tend to involve blood vessels and connective tissues, and therefore, they are often classified as collagen vascular diseases.

158.  Tolerance – a state of unresponsiveness specific for a given antigen  It is specific (negative) immune response  It is induced by prior exposure to that antigen

159.  Self tolerance – prevents the body to elicit an immune attack against its own tissues

160.  Self-non-self discrimination is learned during development  Tolerance is NOT genetically programmed  The time of first encounter is critical in determining responsiveness

161.  Immunological tolerance is unresponsiveness to an antigen  Self-tolerance refers to lack of responsiveness to an individual's own antigens-live in harmony with our cells and tissues.  Lymphocytes capable of recognizing self-antigens are being generated constantly, and these cells have to be eliminated or inactivated as soon as they recognize the antigens, to prevent them from causing harm.

162.  Sites in the body where foreign antigens or tissue grafts do not elicit immune responses  Immunosuppressive cytokines such as TGF-beta seem to be resposible for such unusual response  The sites include: brain, eye, testis, uterus (fetus)

163. The mechanisms of self-tolerance can be broadly classified into two groups:  central tolerance and  peripheral tolerance

164. Central  The site for T cells is the thymus  The site for B cells is the bone marrow  The mechanism – clonal deletion Peripheral  The site – everywhere in the body  Cells – both T and B  Mechanisms – anergy, cell death, immune deviation

165.  immature self-reactive T- and B-lymphocyte clones that recognize self-antigens during their maturation in lymphoid organs are killed or rendered harmless  T lymphocytes - Negative selection or deletion  B lymphocytes - Receptor editing;

166.  developing T cells, random somatic gene rearrangements – TCRs - produces many lymphocytes that express high-affinity receptors for self-antigens.  When immature lymphocytes encounter the antigens + self-MHC by thymic antigen-presenting cells -cells die by apoptosis. This process, called negative selection or deletion,

167.  some of the T-cell lineage cells that see self antigens in the thymus do not die but develop into regulatory T cells  A protein called AIRE (autoimmune regulator) is critical for deletion of immature T cells specific for self antigens  Mutations in the AIRE gene are the cause of an autoimmune polyendocrinopathy

168.  developing B cells recognize self-antigens in the bone marrow,- antigen receptor gene rearrangement  to express new antigen receptors, not specific for self-antigens. This process is called receptor editing;  If receptor editing does not occur, the self-reactive cells undergo apoptosis,

169.  NOT 100 % perfect.  Not all self-antigens may be present in the thymus,  and hence T cells bearing receptors for such autoantigens escape into the periphery.  There is similar “slippage” in the B-cell system.  Self-reactive lymphocytes that escape negative selection - tissue injury unless they are deleted in the peripheral tissues.

170.  Several mechanisms silence potentially autoreactive T and B cells in peripheral tissues  Anergy  Suppression by regulatory T cells  Deletion by activation-induced cell death

171.  Clonal deletion – physical elimination of cells during their lifespan  Clonal anergy – downregulating the intrinsic mechanism of the immune response such as lack of costimulatory molecules or insufficient second signal for cell activation  Suppression – inhibition of cellular activation by interaction with other cells: (Treg – CD4+, CD25+ T lymphocytes )

172.  Anergy: prolonged or irreversible functional inactivation of lymphocytes, induced by encounter with antigens under certain conditions.  activation of antigen-specific T cells requires two signals:  recognition of peptide antigen + self-MHC molecules on the surface of APCs and  costimulatory signals (“second signals”) from APCs.

173.  These second signals are provided by certain T cell–associated molecules, such as CD28, that bind to their ligands (the costimulators B7-1 and B7-2) on APCs.  If APC do not bear the costimulators a negative signal is delivered, and the cell becomes anergic  Anergy also affects mature B cells in peripheral tissues.  if B cells encounter self-antigen in the absence of specific helper T cells, - unable to respond to subsequent antigenic stimulation and may be excluded from lymphoid follicles, resulting in their death.

174. Suppression by regulatory T cells: develop mainly in the thymus, as a result of recognition of self- antigens  CD4+ cells that express CD25, the α chain of the IL-2 receptor, and a transcription factor of the forkhead family, called Foxp3.  The mechanisms to suppress immune responses are not fully defined.  inhibitory activity -mediated by the secretion of immunosuppressive cytokines such as IL-10 and TGF-β, - inhibit lymphocyte activation

175.  Deletion by activation-induced cell death: CD4+ T cells that recognize self-antigens receive signals that promote their death by apoptosis.  T cells recognize self-antigens, they may express a pro-apoptotic member of the Bcl family, called Bim, without anti-apoptotic members of the family like Bcl-2 and Bcl-x  Unopposed Bim triggers apoptosis

177.  A second mechanism involves the Fas-Fas ligand system.  Lymphocytes as well as many other cells express Fas (CD95), a member of the TNF-receptor family.  FasL, a membrane protein that is structurally homologous to the cytokine TNF, is expressed mainly on activated T lymphocytes.  The engagement of Fas by FasL induces apoptosis of activated T  Self-reactive B cells may also be deleted by FasL on T cells engaging Fas on the B cells

178.  Some antigens are hidden (sequestered) from the immune system, - these antigens are located do not communicate with the blood and lymph.  self-antigens in these tissues do not induce tolerance  e.g testis, eye, and brain, - called immune- privileged sites  If the antigens of these tissues are released, for example, as a consequence of trauma or infection, - leads to prolonged tissue inflammation and injury.

179.  Autoimmunity arises from a combination of the inheritance of susceptibility genes, which may contribute to the breakdown of self-tolerance, and  environmental triggers, such as infections and  tissue damage, which promote the activation of self-reactive lymphocytes  create an imbalance between control mechanisms that normally function to prevent self-reactivity

181. Role of Susceptibility Genes  The incidence is greater in twins of affected individuals than in the general population, and greater in monozygotic than in dizygotic twins.  Most autoimmune diseases are complex multigenic disorders.  The greatest contribution is that of HLA genes.  particular MHC alleles affects the negative selection of T cells in the thymus or the development of regulatory T cells

182.  multiple non-MHC genes are associated with various autoimmune diseases.  Some of these genes are disease-specific, but many of the associations are seen in multiple disorders, suggesting  the products of these genes affect general mechanisms of immune regulation and self- tolerance.  Three recently described genetic associations are.

183.  Polymorphisms in a gene called PTPN-22, - encodes a protein tyrosine phosphatase, are associated with rheumatoid arthritis, type 1 diabetes, and several other autoimmune diseases.  phosphatase is functionally defective and is unable to fully control the activity of tyrosine kinases, which are involved in many lymphocyte responses. The net result is excessive lymphocyte activation.

184.  Polymorphisms in the gene for NOD-2 are associated with Crohn disease,  NOD-2 - cytoplasmic sensor of microbes, expressed in epithelial and many other cells.  the disease-associated variant is ineffective at sensing intestinal microbes, -chronic inflammatory responses against normally well-tolerated commensal bacteria.

185.  The genes encoding the IL-2 receptor (CD25) and IL-7 receptor α chains are associated with multiple sclerosis and other autoimmune diseases.  These cytokines may control the maintenance of regulatory T cells.

186.  Many autoimmune diseases and clinical flare- ups are associated with infections,  Two mechanisms  Expression of costimulators on APCs  infections may up-regulate the expression of costimulators on APCs.  If these cells are presenting self-antigens, the result may be a breakdown of anergy and activation of T cells specific for the self- antigens

187.  Molecular mimicry  some microbes may express antigens that have the same amino acid sequences as self-antigens.  Immune responses against the microbial antigens may result in the activation of self-reactive lymphocytes.  Example is rheumatic heart disease, in which antibodies against streptococcal proteins cross- react with myocardial proteins and cause myocarditis

189.  Some viruses, such as Epstein-Barr virus (EBV) and HIV, cause polyclonal B-cell activation, which may result in production of autoantibodies.  The tissue injury that is common in infections may release self-antigens and structurally alter self- antigens to activate T cells -not tolerant to new, modified antigens.  Infections may induce the production of cytokines that recruit lymphocytes, including potentially self- reactive lymphocytes, to sites of self-antigens.

190.  common disease, with a prevalence that may be as high as 1 in 2500 in certain populations  predominantly affects women, with a frequency of 1 in 700 among women of childbearing age and a female-to-male ratio of 9 : 1  2–3 fold higher in blacks and Hispanics than in whites.

191.  Chronic, remitting and relapsing, often febrile multisystem disease of autoimmune origin- vast array of autoantibodies, particularly antinuclear antibodies (ANAs).  characterized principally by injury to the skin, joints, kidney, and serosal membranes.

192. 1997 Revised Criteria for Classification of Systemic Lupus Erythematosus CriterionDefinition 1. Malar rashFixed erythema, flat or raised, over the malar eminences 2. Discoid rashErythematous raised patches with adherent keratotic scaling and follicular plugging; 3. Photosensitivity Rash as a result of unusual reaction to sunlight, 4. Oral ulcersOral or nasopharyngeal painless ulceration 5. ArthritisNonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion 6. SerositisPleuritis or pleural effusion, or Pericarditis or pericardial effusion 7. Renal disorder Persistent proteinuria or Cellular casts—may be red blood cell, hemoglobin, granular, tubular, or mixed

193. 8. Neurologic disorderSeizures or Psychosis—in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance) 9. Hematologic disorderHemolytic anemia—with reticulocytosis, or Leukopenia or Lymphopenia 10. Immunological disorder Anti-DNA antibody, or Anti-Sm—presence of antibody to Sm nuclear antigen, or Positive finding of antiphospholipid antibodies based on (1) an abnormal serum level of IgG or IgM anticardiolipin antibodies, (2) a positive test for lupus anticoagulant or (3) a false-positive serologic test for syphilis known to be positive for at least 6 months and confirmed by negative Treponema pallidum immobilization or fluorescent treponemal antibody absorption test 11. Antinuclear antibodyAn abnormal titer of antinuclear antibody by immunofluorescence in the absence of drugs known to be associated with drug-induced lupus syndrome

195.  A person is said to have systemic lupus erythematosus if any 4 or more of the 11 criteria are present, serially or simultaneously, during any period of observation.

196.  Some antibodies are against nuclear and cytoplasmic components of the cell that are neither organ- nor species-specific, and  others are directed against cell surface antigens of blood cells.  Responsible for the immune complex–mediated glomerulonephritis -typical of this disease  Antinuclear antibodies (ANAs) are directed against nuclear antigens and can be grouped into four categories:  (1) antibodies to DNA,  (2) antibodies to histones,  (3) antibodies to nonhistone proteins bound to RNA, and  (4) antibodies to nucleolar antigens.

197.  The most widely used method for detecting ANAs is indirect immunofluorescence,  The pattern of nuclear fluorescence suggests the type of antibody present in the patient's serum.  Four basic patterns are recognized:  Homogeneous or diffuse nuclear staining - antibodies to chromatin, histones, and, occasionally, double-stranded DNA. Rim or peripheral staining patterns - antibodies to double-stranded DNA.

198.  Speckled pattern one of the most commonly observed patterns of fluorescence - the presence of antibodies to non-DNA nuclear constituents. Examples include Sm antigen, ribonucleoprotein, and SS-A and SS-B reactive antigens  Nucleolar pattern few discrete spots of fluorescence within the nucleus and represents antibodies to RNA

200.  The immunofluorescence test is sensitive because it is positive in every patient with SLE, but not  specific because patients with other autoimmune diseases also frequently score positive  Antibodies to double -stranded DNA and the so- called Smith (Sm) antigen are virtually diagnostic of SLE.

201.  Antiphospholipid antibodies - present in 40% to 50% of lupus patients.  directed against epitopes of plasma proteins - complex with phospholipids.  prothrombin, annexin V, β 2 -glycoprotein I, protein S, and protein C.  Some of these antibodies interfere with in vitro clotting tests, such as partial thromboplastin time. -referred to as lupus anticoagulant.

202.  Despite having a circulating anticoagulant -have complications associated with a hypercoagulable state  venous and arterial thrombosesassociated with recurrent spontaneous miscarriages and focal cerebral or ocular ischemia.  Antibodies against the phospholipid–β 2 - glycoprotein complex also bind to cardiolipin antigen, used in syphilis serology, - have a false- positive test result for syphilis.

203.  the fundamental defect in SLE is a failure of the mechanisms that maintain self-tolerance.

204. Genetic Factors  contributions from MHC and multiple non-MHC genes.  Family history  higher rate (>20%) in monozygotic twins vs dizygotic twins (1% to 3%).  Specific alleles of the HLA-DQ locus - production of anti–double-stranded DNA, anti-Sm, and antiphospholipid antibodies,  inherited deficiencies of early complement components, such as C2, C4, or C1q.

205. Immunological Factors  Failure of self-tolerance in B cells & CD4+ helper T cells - specific for nucleosomal antigens  Nuclear DNA and RNA in immune complexes activate B lymphocytes - function normally to sense microbial products  Other cytokines that may play a role in unregulated B-cell activation include the TNF family member, BAFF

206. Environmental Factors  Exposure to ultraviolet (UV) light exacerbates the disease - induce apoptosis in cells - alter the DNA that it becomes immunogenic,  Sex hormones - reproductive years the frequency of SLE is 10 times greater in women than in men, and exacerbation during normal menses and pregnancy.  Drugs such as hydralazine, procainamide, and D - penicillamine can induce an SLE-like response in humans.

208.  Most of the visceral lesions are caused by immune complexes (type III hypersensitivity).  immune complexes- glomeruli and small blood vessels.  Autoantibodies specific for red cells, white cells, and platelets opsonize these cells -phagocytosis and lysis

209.  LE bodies or hematoxylin bodies. phagocytic leukocyte that has engulfed the denatured nucleus of an injured cell.  used in the past as a test for SLE.

210.  The morphologic changes in SLE are extremely variable.  The most characteristic lesions result from immune complexes depositing in blood vessels, kidneys, connective tissue, and skin.  An acute necrotizing vasculitis - capillaries, small arteries and arterioles - characterized by fibrinoid deposits in the vessel walls.  In chronic stages, vessels undergo fibrous thickening with luminal narrowing.

211. Kidney:  lupus nephritis- immune complex deposition in the in the mesangium or along the entire basement membrane and sometimes throughout the glomerulus, tubular or peritubular capillary basement membranes, or larger blood vessels.  thrombi in glomerular capillaries, arterioles, or arteries

212. Five morphological patterns of lupus nephritis are recognized:  minimal mesangial (class I)  mesangial proliferative (class II)  focal proliferative (class III)  diffuse proliferative (class IV)  membranous (class V)

213. Mesangial lupus glomerulonephritis : 10% to 25% of patients  characterized by mesangial cell proliferation and immune complex deposition without involvement of glomerular capillaries.  There is no or slight (class I) to moderate (class II) increase in both mesangial matrix and number of mesangial cells

214. Focal proliferative glomerulonephritis (class III) 20% to 35% of patients,  <50% of glomeruli involved  may be segmental (affecting only a portion of the glomerulus) or global (involving the entire glomerulus).  Affected glomeruli may exhibit crescent formation, fibrinoid necrosis, proliferation of endothelial and mesangial cells, infiltrating leukocytes, and eosinophilic deposits or intracapillary thrombi - lead to chronic global or segmental glomerular scarring.

215. Focal proliferative type

216.  Diffuse proliferative glomerulonephritis (class IV) - 35% to 60% of patients.  proliferation of endothelial, mesangial and, sometimes, epithelial cells latter producing cellular crescents that fill Bowman's space  >50% glomeruli involved  Membranous glomerulonephritis (class V) -10% to 15%  diffuse thickening of the capillary walls  may occur concurrently with focal or diffuse lupus nephritis.

217. Diffuse proliferative type

219.  variable amounts of mesangial deposits.  In membranous lupus nephritis, the deposits - subepithelial (between the basement membrane and visceral epithelial cells).  proliferative types (classes III and IV) – subendothelial deposits (between the endothelium and the basement membrane)  subendothelial deposits create a homogeneous thickening of the capillary wall, seen by light microscopy as a “wire-loop” lesion - in both focal and diffuse proliferative (class III or IV) lupus nephritis

220. Skin.  Urticaria, bullae, maculopapular lesions, and ulcerations also occur.  Histologically vacuolar degeneration of the basal layer of the epidermis  Vasculitis with fibrinoid necrosis may be prominent.  deposition of immunoglobulin and complement along the dermoepidermal junction skin.  Joints. Non-erosive synovitis with little deformity

221. Central Nervous System. Non-inflammatory occlusion of small vessels by intimal proliferation  which may be due to endothelial damage by antiphospholipid antibodies. Pericarditis and Other Serosal Cavity acute, subacute, or chronic.  During the acute phases- covered with fibrinous exudate-thickened, opaque, and coated with a fibrous tissue - partial or total obliteration of the serosal cavity.

222. Cardiovascular system - damage to any layer of the heart.  pericardial involvement - up to 50% of patients.  Myocarditis - less common  Valvular abnormalities - mitral and aortic valves - diffuse leaflet thickening - stenosis and/or regurgitation.  Valvular (or so-called Libman-Sacks) endocarditis - single or multiple 1- to 3-mm warty deposits on any heart valve, distinctively on either surface of theleaflets  (angina, myocardial infarction) - coronary atherosclerosis. immune complexes and antiphospholipid antibodies -endothelial damage and atherosclerosis.

224.  Spleen Splenomegaly, capsular thickening, and follicular hyperplasia  Lungs. Pleuritis and pleural effusions  chronic interstitial fibrosis and secondary pulmonary hypertension  Other Organs and Tissues. LE, or hematoxylin, bodies in the bone marrow or other organs  Lymph nodes enlarged with hyperplastic follicles

225.  SLE is a multisystem disease  The most common causes of death are renal failure and intercurrent infections

226. Clinical ManifestationPrevalence in Patients (%) [*] Hematologic100 Arthritis80–90 Skin85 Fever55–85 Fatigue80–100 Weight loss60 Renal50–70 Neuropsychiatric25–35 Pleuritis45 Myalgia35 Pericarditis25 Gastrointestinal20 Raynaud phenomenon15–40 Ocular15 Peripheral neuropathy15 Clinical and Pathologic Manifestations of Systemic Lupus Erythematosus

227.  chronic disease characterized by: (1) chronic inflammation - autoimmunity, (2) widespread damage to small blood vessels, and (3) progressive interstitial and perivascular fibrosis in the skin and multiple organs  The skin is most commonly affected, but the gastrointestinal tract, kidneys, heart, muscles, and lungs.  death from renal failure, cardiac failure, pulmonary insufficiency, or intestinal malabsorption.

228. The clinically heterogeneity two major categories:  diffuse scleroderma- widespread skin involvement at onset, with rapid progression and early visceral involvement; and  limited scleroderma- skin involvement confined to fingers, forearms, and face. Visceral involvement occurs late; hence, the clinical course is relatively benign.  Some patents with the limited disease develop the CREST syndrome.  Calcinosis,  Raynaud's phenomenon,  Esop  hageal dysmotility,  Sclerodactyly, and  Telangiectasia

229.  Autoimmune responses,  vascular damage, and  collagen deposition(fibrosis) - tissue injury

231. Abnormal Immune Responses  CD4+ T cells - antigen accumulate in the skin – cytokines - activate inflammatory cells and fibroblasts.  Cytokines including TGF-β and IL-13- transcription of genes - encode collagen and other extracellular matrix proteins (e.g., fibronectin) in fibroblasts.

232.  Two ANAs strongly associated with systemic sclerosis – One directed against DNA topoisomerase (anti-Scl 70), is highly specific.  other, an anticentromere antibody, is found in 20% to 30% of patients- CREST syndrome or limited cutaneous systemic sclerosis.

233. Vascular Damage  Intimal proliferation is evident in 100% of digital arteries  Capillary dilation with leaking, as well as destruction,  Nailfold capillary loops are distorted early in the course of disease- disappear.  Repeated cycles of endothelial injury followed by platelet aggregation lead to release of platelet and endothelial factors (e.g., PDGF, TGF-β) - trigger perivascular fibrosis.

234. Fibrosis  The progressive fibrosis - actions of fibrogenic cytokines produced by infiltrating leukocytes- following upon ischemic damage caused by the vascular lesions.

236.  Prominent changes occur in the skin, alimentary tract, musculoskeletal system, and kidney, but also are often present in the blood vessels, heart, lungs, and peripheral nerves.

237. Skin  diffuse, sclerotic atrophy of the skin begins in the fingers and distal regions of the upper extremities extends proximally to involve the upper arms, shoulders, neck, and face.  perivascular infiltrates  Capillaries and small arteries show thickening, endothelial cell damage, and partial occlusion.  fibrosis of the dermis, which becomes tightly bound to the subcutaneous structures.  Focal or diffuse subcutaneous calcifications may develop,  Loss of blood supply -tips of the fingers undergo autoamputation.

238.  Alimentary Tract. affected in 90% of patients.  Progressive atrophy and collagenous fibrous replacement of the muscularis may develop at any level of the gut - in the esophagus.  The lower two thirds of the esophagus often develops a- rubber-hose inflexibility- gastroesophageal reflux- Barrett metaplasia and strictures.  Loss of villi and microvilli in the small bowel - malabsorption  Musculoskeletal System. Inflammation of the synovium, - hypertrophy and hyperplasia of the synovial soft tissues- fibrosis

239. Kidneys. vascular lesions.  Interlobular arteries- intimal thickening - deposition of mucinous or finely collagenous material, - concentric proliferation of intimal cells. Lungs.  pulmonary hypertension and interstitial fibrosis.  Pulmonary vasospasm, secondary to pulmonary vascular endothelial dysfunction Heart  Pericarditis with effusion and myocardial fibrosis,

240.  Female: male ratio of 3 : 1,  50- to 60-year age group.  Raynaud's phenomenon, - vasoconstriction of the arteries and arterioles of the extremities  Dysphagia - esophageal fibrosis – hypomotility  Abdominal pain, intestinal obstruction, or malabsorption syndrome with weight loss and anemia - involvement of the small intestine.  Respiratory difficulties caused by the pulmonary fibrosis may result in right-sided cardiac dysfunction,  and myocardial fibrosis may cause either arrhythmias or cardiac failure.  Mild proteinuria  malignant hypertension,

241.  RHEUMATOID ARTHRITIS chronic inflammatory disease that affects primarily the joints but may involve extra-articular tissues such as the skin, blood vessels, lungs, and heart.  INFLAMMATORY MYOPATHIES  heterogeneous group of disorders characterized by injury and inflammation of mainly the skeletal muscles,  Three distinct disorders,  dermatomyositis,  polymyositis, and  inclusion-body myositis .

242.  MIXED CONNECTIVE TISSUE DISEASE  a disease with clinical features that are a mixture of the features of SLE, systemic sclerosis, and polymyositis  antibodies to ribonucleoprotein particle–containing U1 ribonucleoprotein  POLYARTERITIS NODOSA AND OTHER VASCULITIDES  necrotizing inflammation of the walls of blood vessels

243.  characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia)  immunologically mediated destruction of the lacrimal and salivary glands.  It occurs as an isolated disorder (primary form), also known as the sicca syndrome,

244.  more often in association with another autoimmune disease (secondary form).  rheumatoid arthritis - most common, but  some patients have SLE, polymyositis, scleroderma, vasculitis, mixed connective tissue disease, or thyroiditis

245.  The decrease in in tears and saliva (sicca syndrome) is the result of lymphocytic infiltration and fibrosis of the lacrimal and salivary glands  About 75% of patients have rheumatoid factor (an antibody reactive with self-IgG)  ANAs are detected in 50% to 80% of patients.  antibodies directed against two ribonucleoprotein antigens, SS-A (Ro) and SS-B (La)

246.  The initiating trigger - viral infection of the salivary glands- cell death and release of tissue self- antigens.  In genetically susceptible individuals, CD4+ T cells and B cells specific for these self-antigens - escaped tolerance- inflammation, tissue damage, and, eventually, fibrosis.  A cytoskeletal protein called α-fodrin - autoantigen, but its role not defined  The viruses initiating stimuli are -Epstein-Barr virus, and hepatitis C virus

247.  salivary glands - periductal and perivascular lymphocytic infiltration- lymphoid follicles with germinal centers may be seen.  The ductal lining epithelial cells may show hyperplasia- obstructing the ducts.  atrophy of the acini, fibrosis, and hyalinization  The lack of tears - drying of the corneal epithelium- inflamed, eroded, and ulcerated;  the oral mucosa -inflammatory fissuring and ulceration;  and dryness and crusting of the nose - ulcerations and perforation of the nasal septum.

248. Sjögren syndrome