IMMUNOLOGY - an overview

Brief introduction to immunology and Importance of the immune system in health and disease.

1. SEMINAR TOPIC : IMMUNOLOGY PRESENTED TO : PROF. and HOD (Dr.) ALTAF HUSSAIN CHALKOO PRESENTED BY: BAZILA ILLAHI FIRST YEAR POSTGRADUATE DEPT.OF ORAL MEDICINE AND RADIOLOGY

2. CONTENTS INNATE IMMUNITY ADAPTIVE IMMUNITY IMMUNE RESPONSE PRINCIPAL CELLS OF IMMUNE SYSTEM ANTIGEN ANTIBODY COMPLEMENT SYSTEM MHC AND ASSOCIATED DISEASES CYTOKINES INTERFERONS IMMUNE SYSTEM IN ORAL CAVITY DISORDERS OF IMMUNE SYSTEM IMMUNODEFICIENCY AUTOIMMUNE DISEASE AUTOIMMUNE DISEASES OF OROFACIAL REGION IMMUNOSURVEILLANCE

3. Innate vs adaptive immunity

4. IMMUNITY Immunity is the resistance exhibited by the host towards injury caused by microorganisms or their products. These are of two types Innate immunity( native immunity) Adaptive immunity( acquired immunity) INNATE IMMUNITY Virtue of individuals genetic and constitutional make up. First line of defense against microorganisms. Present since birth . Not affected by prior contact with microorganisms or immunization. Antigen exposure is not required.

5. Immunological memory is not present. It is not specific , it is active against wide range of infectious agents. Important components of innate immune system: Cells :macrophages, dendritic cells,NK cells,neutrophils,eosinophils,mast cells,basophils,epithelial cells. Complement components :classical and alternate pathways. Antimicrobial : peptides:defensins,cathelin,probiotics,protegrin,ganulysin,histatin,leukoprotease inhibitor. Pattern recognition receptors :C type lectins,leucin -rich proteins,scavenger receptors,pentraxins,lipid transferases,integrins

6. ADAPTIVE (ACQUIRED) IMMUNITY: It is found only in vertebrates. It is based on generation of antigen receptors on T and B lymphocytes by germ line gene rearrangement. It is specific It is developed as a result of an antigenic stimulus( immunological priming) or by passive transfer of antibodies It provides immunological memory Subsequent antigen exposure leads to more rapid and vigorous immune response. The adaptive immune system consist of dual limbs of cellular and humoral immunity. CELL MEDIATED HUMORAL MEDIATED T- cells B-cells plasma cells antibodies

7. Adaptive immunity is of following types:- ACTIVE IMMUNITY Host’s immune system actively produces immunity. Antigenic stimulus induces the immune system to produce antibodies or cellular immune response. Active immunity may be: a) NATURAL :due to infection (either clinical or subclinical) b )ARTIFICIAL : vaccination( immunization) 2) PASSIVE IMMUNITY Antibodies are produced by another organism and then received passively by the host.

8. Passive immunity may be:- NATURA L-transport of antibodies across the placenta from mother to fetus. ACQUIRED -administration of immunoglobulins/antibody ADAPTIVE IMMUNITY A special type of immunization. In which immunologically competent lymphocytes are injected. These lymphocytes are known as transfer factor. Used in the treatment of lepromatous leprosy.

9. Comparison of active and passive immunity Active immunity Produced actively Induced by infection Durable effective protection Effective only after a lag period Immunological memory present Booster effect on subsequent doses Negative phase may occur Not applicable in immunodeficiency Passive immunity No active participation Ready made antibodies transferred Transient,less effective Immediate immunity No memory Subsequent doses less effective No negative phase Applicable in immunodeficiency

10. immune response Primary response Slow Sluggish Short lived Long lag phase Predominant IgM Antibody is more specific Antibody is less avid Qualitative response Secondary response Fast Powerful Prolonged Short or negligible lag phase Predominant IgG Antibody is less specific Antibody is more avid Quantitative response

11. PRINCIPAL CELLS OF IMMUNE SYSTEM AND THEIR FUNCTION

12. T lymphocyte

13. T-LYMPHOCYTES(THYMUS DERIVED) Constitute 60-70% of peripheral blood lymphocytes. Located in the paracortical areas of lymphnode and periarteriolar sheaths of spleen. Cells have an antigen specific T cell receptor to bind with the antigen. The alpha beta T cells are present in blood and tissues. The other 5% with gamma delta chains are present mostly at the epithelial/mucosal surface

14. When an antigenic peptide comes in contact with TCR ,it activates a particular T cells only. This is called clonal selection The cells have on their surface CD molecules. By which they can be readily identified The CD molecules present on T cells are CD1,CD2,CD3,CD4,CD5,CD6,CD7,CD8 and CD28 CD4 cells are called helper T cells. Are known as master regulator of immune system. Helper T cells secrete cytokines which regulate macrophages and B cells. CD8 T cells destroy host cells having microbes like viruses and tumour cells

15. The ratio of CD4 and CD8 –T cell is normally 2:1 CD3 is involved in signal transduction ,is also known as pan T cell marker. Activation of T cells require two signals Activated T cells gives rise to two groups of cells:effector cells and memory cells.

16. ANTIGEN PRESENTING CELLS When antigen presenting cells phagocytose the antigen, they process the antigen and present it on their surface in association with MHC molecule. This processed antigen is now presented to the T cells. The part of the antigen associated with MHC molecule on the APC , is called aggretope Whereas the antigenic part in contact with TCR is called epitope. Antigen presenting cells include: Macrophages,dendritic cells, B cells

17. Epitope and paratope

18. macrophages

19. Macrophages These cells have role in induction and effector phase of immune response. They process and present the antigen to T cells for induction of CMI. They get activated by the presence of IFN-gamma They are effector cells in humoral immunity as they phagocytose opsonized microbes.

20. Dendritic cells Interdigitating dendritic cells The most important APCs For initiating primary immune response against protein antigens. Follicular dendritic cells Present in germinal centers of lymphoid follicles, in the spleen and lymph nodes. These cells bear Fc receptors for IgG and receptors for C3b They can trap antigen bound to antibodies or complement proteins. These cells are required for the process of affinity maturation.

21. Nk cells

22. NATURAL KILLER CELLS(NK CELLS) OR NULL NK CELLS: NK cells also called ‘large granular lymphocytes’. Morphologically larger than both T and B lymphocytes. First line of defence against cancer and virus infected cells. Contain azurophilic granules. Constitute 5-10% of peripheral blood lymphocytes. They arise in both bone marrow and thymic microenvironments. NK cells are activated in the presence of IL-2. Hyporesponsive NK cells are found in chediak -higashi syndrome.

23. B lymphocytes

24. B-LYMPHOCYTES( BONE MARROW DERIVED) Constitute 10 to 20% of peripheral blood lymphocytes. Located in the cortical areas of lymph node,white pulp of spleen and mucosa associated lymphoid tissue of pharyngeal tonsils and peyer’s patches of GIT. These cells have B cell receptor. Composed of IgM and Ig G on their surface to bind with the antigen. BCR has unique antigen specificity The rearrangement of Ig gene can give rise to different types of BCR. The antigen however binds to the complementary BCR only(clonal selection) B cell associated markers are CD10,CD19,CD20,CD21,CD22,CD23.

25. antigen

26. ANTIGEN: Is a foreign or self molecule that are recognized by immune system Resulting in production of antibody or induction of cell mediated immunity or both. Antigens may be:- Complete antigen Complete antigen is able to induce antibody formation. Hapten Incapable of inducing antibody formation by themselves, but can react specifically with antibodies. Hapten becomes immunogenic on combining with a larger molecule carrier, i.e. it requires carrier for specific antibody production.

27. Haptens are of two types: Simple hapten - it is monovalent and cannot precipitate with specific antibody. Complete hapten -it is polyvalent and can precipitate with specific antibody. Epitope (antigenic determinant) is the antigen binding site of antigen.It is the smallest unit of antigenicity. Complementary region of epitope on antibody , i.e.antigen binding site of antibody is called paratope(or idiotope ).

28. TYPES OF ANTIGEN Antigens may be of following types: Based on chemical nature Proteins : most immunogenic,while lipids and nucleic acids are least immunogenic. Polysaccharides (carbohydrates): are less immunogenic than proteins. All proteins except gelatin are immunogenic. Based on immune response T-cell dependent antigens. T-cell independent antigens.

29. protein antigen vs carbohydrate antigen Protein antigen More immunogenic T-cell dependent No tolerance Induce production of all types of antibodies Memory response is seen Require processing by APCs. Quickly metabolized Carbohydrate antigen Less immunogenic T-cell independent Immunological tolerance occurs Induce production of IgM and IgG only No memory response Do not require processing Slowly metabolized

30. SUPERANTIGENS Potent activators of T-lymphocytes Stimulate very large number of T cells Without relation to their epitope specificity This leads to an excessive and dysregulated immune response With release of cytokines IL-1,IL-2,TNF-alpha and IF- gamma They are gamma beta restricted T cell mitogens Capable of activating upto 20% of the peripheral T-cell pool Conventional antigens activate <1 in 10,000 Antigen Specificity of TCR is not required Antigen presentation is not required for superantigens

31. Autoantigens Autologous or self antigens are nonimmunogenic. But there are some exceptions. Some sequestered antigens that are normally not found in circulation or tissue fluid are not recognized as self antigens. Examples are eye lens protein sperm Adjuvants : Any substances that enhances the immunogenicity of an antigen.

32. antibody

33. Antibody structure

34. ANTIBODIES Immunoglobulins are molecules that are produced by plasma cells in response to an immunogen. Are glycoproteins Composed of two light chains (L) and two heavy chains (H). The L chain has M.W of 25,000 and H chain of 50,000. The L chains is attached to H chain by disulphide bond. The two H chains are joined together by disulphide bonds. Immunoglobulin isotype (i.e. G,M,A,D,E) is determined by the type of Ig heavy chain present. Hinge point is the point at which heavy and light chains join. This point can be digested by papain digestion To produce one Fc fragment and two Fab fragments.

35. The isotype variation or class of antibody is due to variation in the amino acid sequences in the constant region of the heavy chain. There are five potential variation in the aminoacid sequence in the constant region there are five classes of antibody i.e.IgG,IgM,IgA,IgD,IgE . The L chain are similar in all classes of immunoglobulins either kappa or lambda. Antigen combining site is at amino-terminus and is composed by both L and H chains. Both H and L chains are composed of two units ;constant and variable: The variable region is further subdivided into hypervariable region and frame work region. Hypervariable regions at aminoterminal are involved in the formation of antigen binding sites.

36. L chain has 3 hypervariable regions and H chain has 4 hypervariable regions. Complementary determining regions –sites on hypervariable regions which will make actual contact with the epitopes. Infinte range of the antibody specificity of immunoglobulins depends on the variability of the aminoacid sequences at the variable units of H and L chains. Fc fragment is composed of the carboxyterminal. It determines the biological activity such as: Complement fixation, placental transfer, skin fixation and catabolic rate. Isotype switching: Isotype switching is a biological mechanism that changes a B cells ’ production of antibody from one class to another. For example IgM in primary response to IgG in secondary response.

37. Types of antibodies

38. Individual antibodies IgM It is the oldest immunoglobulin class. It is the predominant antibody in primary response. IgM is the earliest immunoglobulin class to be synthesized by fetus. Beginning at 20 weeks of age. It is not transported across the placenta. The presence of IgM in the fetus or newborn indicates intrauterine infections. Its detection is useful in the diagnosis of congenital infections such as syphilis,rubella and toxoplasmosis. Normally circulates as a pentamer. Is a pentavalent immunoglobulin.

39. The isohemagglutinins (blood group anti A,anti B) are usually IgM. Monomeric IgM is the major antibody receptor on the surface of B lymphocytes for antigen recognition. IgM is an important component of immune complex in autoimmune diseases e.g.IgM antibodies against IgG in rheumatoid arthritis. Most effective antibody in complement fixation ( specifically classical pathway) and for opsonization. IgG Major serum immunoglobulin (80%). Equal distribution between IV and EV compartments. Contains < carbohydrates than other Igs Has maximum half life of 23 days

40. Binds to microorganisms and enhances their phagocytosis. Considered as general purpose antibody. Predominant antibody in secondary antibody response. Four subclasses of IgG with relative concentration IgG1 >IgG2 >IgG3 >IgG4 IgG1,IgG3 and sometimes IgG2 activate classical complement pathway. IgG4 activates alternate complement pathway. Only maternal immunoglobulin that is normally transported across the placenta. Provides natural passive immunity in the newborn.

41. IgG production reaches at normal level ,once healthy babies reach six months of age. IgG is more effective than IgM for: Neutralization of toxins and viruses Precipitation reactions IgA Second most abundant antibody after IgG. It is major immunoglobulin in colostrum,saliva,tears,respiratory and GIT secretions. Occurs in two forms

42. Serum IgA: monomer and is found in serum. Secretory IgA :dimer ,joined by j chain ,contains glycine rich polypeptide. Serum IgA and j chain are synthesized by plasma cells. Secretory component is produced by mucosal or glandular epithelial cells IgE (REAGIN ANTIBODY) Heat labile( inactivated at 56 degree centigrade in 1 hour) Affinity for the surface of tissue cells( mast cells) Homocytotropic( species specific) Can not be demonstrated by the conventional serological reactions .

43. Detected by- Radioallegosorbent test(RAST) ELISA Passive agglutination Chiefly produced in the lining of respiratory and intestinal tract. Responsible for anaphylactic type of hypersensitivity. Elevated in- Atopic conditions(type 1 hypersensitivity) Parasitic infection Anaphylaxis

44. COMPLEMENT SYSTEM AND ITS PATHWAYS

45. COMPLEMENT SYSTEM Classical activation pathway Mannose- binding lectin activation pathway Alternate activation pathway Terminal pathway( leads to membrane attack complex) The central process in the complement cascade is the activation of C3. Major component of complement: In classical pathway C3 convertase is C4b2a In alternate pathway C3 convertase is C3bBb C3 convertase acts on C3

46. Physiological actions of complement components C5a,C3a and to a lesser extent C4a are called anaphylotoxins They have effects similar to those of mast cell mediators. That are involved in the reactions called anaphylaxis. The effects are increased vascular permeability and vasodilatation. C5a is a powerful chemotactic agent. C3b,C3bi act as opsonins and enhance phagocytosis. C5-9 is called as membrane attack complex(MAC). It forms channel in the lipid memebrane and causes cell lysis

47. C3 convertase acts on C3. Splits it into two fragments C3a and C3b. C5 is the point where both classical (antibody dependent) and alternate (antibody independent) pathways converge. Thus C5 forms the final common terminal pathway. IgM is the most effective antibody to fix complement. In classical pathway all components are consumed ( C1 to C9) In alternative pathway all components are consumed except C1,C2 and C4.

48. Synthesis and regulation of complement system Complement components are proteins. C1 is synthesized in intestine. C2 and C4 are synthesized by macrophages. C5 and C8 are synthesized in spleen. C3,C6 and C9 are synthesized in liver.

49. Regulatory molecules of complement system Decay accelerating factor (DAF) increases the dissociation of C3 convertase. Factor I proteolytically cleaves C3b. CD59( membrane inhibitor of reactive lysis) inhibits formation of MAC. Factor H,factor I,and CD46 prevent excessive alternate pathway activation. IgM and IgG are responsible for activation of classical pathway where as IgA is responsible for activation of alternate pathway. Deficiency of C2 is the most common complement deficiency .

50. Deficiency of complement and disease/syndrome Deficiency of complement DISEASE/SYNDROME C1 esterase inhibitor . hereditary angioneurotic edema C1,c2,c4 deficiency . SLE and collagen vascular disease C3b and C3bi inactivator . recurrent pyogenic infections C5 to C8 . bacterial infections with Neisseria and . toxoplasmosis 5. C9 . no particular disease 6 . DAF and CD59 . PNH 7. CD46,factor H and I . atypical hemolytic uremic syndrome

51. opsonization

52. Opsonization : The coating of an antigen or particle by a substance, such as antibodies,complement components and fibronectin facilitate phagocytosis. Substance which enhances phagocytosis is called opsonin. Most important opsonins are; antibodies ( IgM,IgG ) complement (C3b)

53. Antigenic interaction with B cell and T cell The activation of T cells requires two signals: Signal 1:comes from binding of the TCR to MHC bound antigen. Signal 2:comes from the interaction of CD28 With co-stimulatory molecules B7-1 and B7-2 present on the antigen presenting cells Competence signal :it is due to interaction between CD40 molecules on B cells with CD 40 ligand on T helper cells. It results in the release of cytokines like IL-4 and IL-5. These cytokines cause B cell proliferation resulting in formation of plasma cells and memory cells

54. CELL MEDIATED IMMUNITY Important for intracellular pathogens,virus infected cells,malignant cells and endogenous antigens. Mediated by CD8 T cells, macrophages,and natural killer cells. Endogenous antigen is expressed with MHC I molecule by nucleated cells. These cells are also destroyed in the process. So these cells are named as target cells and not APCs. Antigen activated CD8 cells undergo proliferation They release perforin-granzyme molecules and express Fas ligand. Both of which initiate apoptosis of target cells.

55. Cell mediated immunity

56. MHC :present on small segment of chromosome 6 with a function of displaying fragments of protein antigens for recognition by antigen specific T cells. Class i gene Comprised of HLA-A,B,C,E,F and G loci Codes for MHC 1 molecule Present on nucleated cells and platelets Detected by alloantisera Present antigen to CD8 cells Require for virus infected cells,cancer cells and graft rejection Class ii gene Comprised of HLA-D locus Code for MHC II molecule Present on B cells, macrophages ,dendritic cells,endothelial cells,fibroblasts Detected by mixed lymphocyte reaction Present antigen to CD4 T cells Require for graft versus host response Class iii gene Codes for complement proteins C2 and C4;TNF-alaphaand beta,heat shock protein,properidin and 21 hydroxylase enzyme. Involved in autoimmune disorders

57. HLA AND DISEASE ASSOCIATION B-27 Psoriatic arthritis Ankylosing spondylitis IBD arthritis Reiters syndrome B-8 Graves disease Myasthenia gravis B-51 Behcets disease B-47 Congenital adrenal hyperplasia CW6 Psoriasis vulgaris

58. HLA-class II disease associations DR-2 Japanese SLE Multiple sclerosis Goods pasture syndrome DR-3 Myasthenia gravis Graves disease Dermatitis herpetiformis Sjogrens syndrome DR-4 Pemphigus vulgaris Rheumatoid arthritis DR-5 Juvenile arthritis DQ-1 Pemphigus vulgaris DQ-7 Bullous pemphigoid

59. CYTOKINES Cytokines are soluble proteins(polypeptides). They are produced by a variety of hematopoietic and non-hematopoietic cell types. They regulate immunological ,inflammatory and reparative host responses. Cytokines mediate their effects by binding to specific high affinity receptors. Specific cytokines mediate specific reactions. Some important cytokines-IFN-alpha and beta ,TNF alpha and beta,LT,IL-1,IL-2,IL-3,IL-4,IL-5,IL-7.

60. Cytokines

61. TYPES OF CYTOKINE PROINFLAMMMATORY CYTOKINES: Involved in amplification of inflammation. Major proinflammatory cytokines are IL-1,TNF-alpha and IL-6. IL-1 is the most important cytokine responsible for systemic effects of inflammation. ANTI-INFLAMMMATORY CYTOKINES These are involved in resolution of inflammation. Examples are IL-4,IL-10,IL-13 and transforming growth factor –beta. IL-4 has mainly anti-inflammatory property with some proinflammatory action. TGF-beta is the most important fibrogenic factor.

62. PYROGENS Pyrogens are substances that cause fever. Pyrogens may be exogenous or endogenous. Exogenous-bacterial toxins Endogenous-IL-1,TNF-alpha,IL-6,interferons,ciliary neurotropic factor. These pyrogens increase the level of PGE2 in the hypothalamus. That elevate the thermoregulatory set point and cause fever.

63. INTERFERON Family of host coded proteins. Produced by cells on induction by viral or nonviral inducers. Interferon production is a natural defence mechanism possessed by vertebrate cells against viral infections. Interferons are protein,either glycosylated or nonglycosylated . Three important interferons are:- IFN-alpha: Nonglycosylated protein Produced by leukocytes

64. IFN-beta Glycoprotein,produced by fibroblasts and epithelial cells. IFN-gamma Glycoprotein,produced by T lymphocytes. MECHANISM OF ACTION Interferon by itself has no direct action on viruses. But it acts on other cells of same species. Rendering them refractory to viral infection. On exposure to interferon,cells produce a protein translation inhibiting protein,which selectively inhibits translation of mRNA.

65. CHEMOKINES Family of small proteins that act primarily as chemoattractants For specific type of leukocytes Classified into 4 major groups According to the arrangement of conserved cysteine(C) residues in mature proteins. C-X-C(alpha chemokines)- primarily act on neutrophils e.g.IL-8,IL-1& TNF. C-C (beta chemokines)- attract all leukocytes except neutrophils e.g. Eotoxin,MCP-1,RANTES,MIP-1a C-chemokine(gamma)- specific for lymphocytes e.g. lymphotactin CX3C chemokine -promote strong adhesion between monocytes and T-cells.

66. chemokines

67. IMMUNITY IN ORAL CAVITY

68. Components of oral immunity

69. Disorders of immune system Hypersensitivity reactions Type I hypersensitivity reaction/anaphylactic type/immediate type Rapidly developing immunological reaction Occurring within minutes It is commonly referred to as allergy Occurs in two steps-first step (the stage of sensitization) and second step. Second step occurs as initial phase and late phase Histamine is responsible for early clinical features . PAF is the major mediator of late phase reaction

70. Types of hypersensitivity rxns .

71. Anaphylactoid reaction: Occurs on first antigenic exposure, short lived , involves degranulation of mast cells but no cytokine synthesis. Examples Localized Systemic Bronchial asthma Anaphylaxis due to: Hay fever/allergic rhinitis antibiotics-most commonly penicillin Food allergies bee stings Atopic dermatitis insect bites Urticaria angioedema

72. MAST CELL MEDIATOR

73. MECHANISM OF TYPE I HyPERSENSITIVITY

74. Type II HYPERSENTIVITY REACTION/ANTIBODY MEDIATED/CYTOLYTIC Mediated by antibodies and is localized to a single tissue or organ. The effector mechanisms for this reaction include Opsonization and complement-and Fc receptor-mediated phagocytosis Complement and Fc receptor-mediated inflammation Antibody mediated cellular dysfunction Examples Myasthenia gravis rheumatic fever Blood transfusion reactions hyperacute graft rejection Goodpasture syndrome pernicious anemia and pemphigus Graves disease ITP

75. ANTIBODY MEDIATED INJURY

76. Type III hypersensitivity reaction or immune complex disease Occurs in three phase- Phase I or immune complex formation-antibody forms about 5 days after antigenic exposure. Phase II or immune complex deposition Phase III-immune complex mediated inflammation seen after 10 days after antigen administration Examples Arthus reaction SLE,HSP(HENOCH SCHONLEIN PURPURA) Farmers lung post streptococcal glomerulonephritis Polyarteritis nodosa serum sickness

77. TYPE IV OR CELL MEDIATED HYPERSENSITIVITY Initiated by antigen activated (sensitized) T lymphocytes. It includes delayed type hypersensitivity reactions mediated by CD4 T cells. And direct cell cytotoxicity mediated by CD8+ T cells. The term delayed is used to differentiate it from a secondary cellular response. Which appears at 48-72 hours after antigen exposure, and from an immediate hypersensitivity response, which generally appears within minutes. Major mechanism of defence against various intracellular pathogens , including mycobacteria , fungi,and certain parasites.

78. Characterized by formation of granuloma. It is also called as granulomatous inflammation Induction of TH1 is of central importance Examples Tuberculin reaction lepromin test Crohn’s disease Chronic graft rejection contact dermatitis Sarcoidosis Temporal arteritis resistance to viral infections Tumor immunity multiple sclerosis

79. TRANSPLANT REJECTION It is a complex process in which both cellular and humoral immunity plays a role. T cell mediated rejection has two pathways-direct and indirect. Direct pathway involves both CD4 and CD8 T cells and cause graft tissue damage by perforin –granzyme and Fas-Fas ligand pathway. Direct pathway is important for acute graft rejection. Indirect pathway, dendritic cells of the recipient present the antigen to CD4 T cells. There is no involvement of the CD8 T cells.

80. Antibody mediated rejection or humoral rejection/rejection vasculitis Takes place by two mechanisms Hypeacute rejection -preformed anti-donor antibodies present in the circulation of recipient. Takes places within minutes to hours Associated with previous blood transfusions,multiparous lady, or already rejected transplant It is an example of type II hypersensitivity reaction. Acute rejection -seen within days to months after transplantation. Includes inflammation , complement dependent cytotoxicity and ADCC(antibody dependent cell cytotoxicity) Initial target of the antibodies is the graft vasculature

81. POSSIBLE COMPLICATIONS OF BONE MARROW TRANSPLANTATION Oral complications : mucositis,mucosal ulcerations,infections,haemorrhage,xerostomia,and parotitis. Gingival hyperplasia if cyclosporin is used. In children,dental hypoplastic defects may develop. Graft –versus-host disease. Systemic infections(sometimes by oral bacteria)-chief cause of death. Tumours such as Kaposi’s sarcoma or lymphoma.

82. Graft versus host disease (GVHD)/RUNT disease ( in animals) Occurs in any situation in which immunologically competent cells or their precursors are transplanted into immunologically crippled patients and the transferred cells recognize allo antigens in the host. It occurs most commonly in the setting of allogenic bone marrow transplantation. When such recipients receive normal bone marrow cells from allogenic donors. The immunocompetent T cells present in the donor marrow recognise the recipients’s HLA antigen as foreign antigen and reacts against them. Both CD4+ and CD8+ cells recognize and attack host tissues.

83. gvhd

84. ACUTE GVHD GVHD developing within the first three months post transplant is termed as acute GVHD. Characterized by an erythematous maculopapular rash;persistent anorexia or diarrhoea,or both Liver disease with increased serum levels of bilirubin,alanine and aspartate aminotransferases,and alkaline phosphatase. Diagnosis requires skin,liver,or endoscopic intestinal biopsy for confirmation In all these organs ,endothelial damage and lymphocytic infiltrates are seen. No treatment is required for Grade I acute GVHD. Therapy is required for grades II to IV GVHD.

85. CHRONIC GVHD GVHD developing or persisting beyond 3 months post transplant . Resembles an autoimmune disorder Characterised by malar rash,sicca syndrome,arthritis,obliterative broncholitis , bile duct degeneration and cholestasis. Susceptible to significant infections, require prophylactic trimethoprim-sulfamethoxazole . Infection with cytomegalovirus is particularly important. The risk of graft versus host can be decreased by depletion of T cells from graft

86. IMMUNODEFICIENCY Results when immune system is not capable of mounting a normal immune response. May be hereditary ,or, Secondary to infections, cancer, diabetes, alcoholism ,or as a consequence of immunosuppressive medications The number of patients is increasing as the life span of people is increasing

87. Warning signs of primary immunodeficiency: The presence of 2 warning signs may indicate an underlying primary immunodeficiency: ≥ 4 new ear infections within 1 year ≥ 2 serious sinus infections within 1 year ≥ 2 months on antibiotic with little effect ≥ 2 pnemonias within 1 year Failure of an infant to gain weight or grow normally Recurrent, deep skin or organ abcesses Persistent thrush in mouth or fungal infection on skin Need for intravenous antibiotics to clear infections ≥ 2 deep-seated infections,including septicemia A family history of primary immune deficiency

88. DEFICIENCIES IN ADAPTIVE IMMUNITY Severe combined immunodeficiency(SCID): Children born with SCID are profoundly immunocompromised Most die before the age of 1 year without treatment Profound deficiency of T-lymphocytes Decreased levels of serum immunoglobulin are common Affected children are susceptible to infection with multiple bacteria,viruses,and fungi Many types of genetic defects can result in SCID ADA(adenosine deaminase) deficiency, yc subunit of cytokine receptors,mutation in RAG1 or RAG2,IL-7 receptor,CD3e and CD3d chains.

89. HSCT(HEMATOPOEITIC STEM CELL TRANSPLANTATION) - is the standard treatment for these children. More successful if performed early. Screening of newborns for SCID includes quantification of T-cell receptor excision circles. ORAL COMPLICATIONS Apthous like ulcerations Candidiasis Herpetic infections

90. Wiskott -Aldrich syndrome: Rare X-linked recessive genetic condition Commonly includes immunoglobulin M (IgM) deficiency. This disorder is a severe congenital immunodeficiency,found exclusisvely in boys. Characterised by: thrombocytopenia microcytic platelets eczema recurrent infections increased incidence of autoimmune disease and malignancies. Clinical manifestations of classic WAS that occur shortly after birth

91. wiskott Aldrich syndrome

92. Clinical manifestations of classic WAS that can occur shortly after birth include petechiae bruising bloody diarrhea otitis media skin infections pneumonia from bacteria Other complications such as autoimmune hemolytic anemia,autoimmune neutropenia, and vasculitis.

93. Central defect in the WAS is a defect in the WAS gene. Mutations can affect both T and B cells,as well as platelets. ORAL MANIFESTATIONS Purpura oral bleeding Candidiasis Herpetic infections Patient may have undergone splenectomy to increase platelet numbers and reduce bleeding episodes. Therefore ,antibiotic prophylaxis may be indicated for more invasive procedures.

94. DECREASE IN CERTAIN CLASS OF Igs WITH NORMAL OR LOW NUMBER OF B CELLS Common variable immunodeficiency disorders ( CVID) CVID is a group of diseases characterized by an inability to produce sufficient levels of antibodies,particularly IgG and IgA. Have normal or near normal number of B cells in the blood and lymphoid tissues which are not able to differentiate into plasma cells. Patients have intrinsic B cell defects and T cell mediated regulation of B cells Defective cytokine receptor called BAFF which normally promotes B cell differentiation and survival.

95. The clinical manifestations include sinopulmonary pyogenic infections recurrent herpesvirus infections persistent diarrhea ( G.lamblia ) No gender predominance Onset of symptoms is relatively late( in childhood or adolescence) These patients have high frequencies of autoimmune diseases like rheumatoid arthritis Also increased risk of lymphoid malignancy such as non-Hodgkin lymphoma that are often in mucosal areas Patients may have immune thrombocytopenia.

96. Selective immunoglobulin deficiencies Characterised by an inability to produce a single class of antibody Varied clinical presentation. Most common immunodeficiency is selective IgA deficiency Occuring 1 of 155 to 1 of 18,500. Some people are healthy ,others have chronic respiratory and GIT infections Autoimmune diseases like SLE,RA,pernicious anemia are more common in this deficiency. Developmentally ,B cell maturation in IgA deficiency is impaired. As secretory IgA is major Ig of saliva ,increase in caries of deciduous teeth.

97. Characterised by significantly elevated IgE levels. Recurrent skin and pulmonary infections.may be autosomal recessive or autosomal dominant. Autosomal dominant forms are due to mutations in STAT3. Autosomal recessive forms are due to mutations in DOCK8. AUTOSOMAL DOMINANT HIES: Characterised by the triad of- eczematoid dermatitis recurrent skin infections recurrent pulmonary infections HYPER-IGE SYNDROMES/JOB’S SYNDROME

98. Oral features: Increased suceptibility for fungal infections Upto 80% are affected with chronic mucocutaneous candiasis Saliva of individuals with HIES has low levels of critical candidacidal peptides. Craniofacial and dental features of HIES Unique facial features Note in late childhood and early adolescence They involve assymetric facies prominent forehead

99. Prominent chin increased interalar width wide-set eyes coarse skin craniosynostosis Chiari 1 malformations delayed exfoliation of teeth high-arched palate with central ridges and fissures deep grooves and fissures on tongue and buccal mucosa

100. Autosomal recessive hyper- IgE syndromes/jobs syndrome Features are similar to AD-HIES but they lack the skeletal features of jobs Oral manifestations are - persistent herpes simplex orolabial infections - abscesses - orofacial squamous dysplasia - carcinoma in patients with long standing HSV infections

101. Selective IgA deficiency Common and potentially relevant for mouth. As IgA is the only Ig secreted in saliva Prevalence is 1 in 600. There is no clear evidence of any significant association between oral mucosal infections and IgA deficiency. Enhanced susceptibility to respiratory tract infections. Atopic diseases- asthma,eczema or any other related diseases may be the first sign Connective tissue diseases ,especially SLE.

102. X-LINKED AGAMMAGLOBULINEMIA OR BRUTONS DISEASE X-linked immunodeficiency disorder Characterised by the failure of B-cell precursor to mature into B cells. Due to maturation of B-cell tyrosine kinase Disease is seen almost entirely in males. Recurrent bacterial infections of respiratory tract are common Causative organisms are Hemophilus influenza,streptococci pneumonia or staphylococcus aureus in most cases.

103. Brutons disease

104. DIGEORGE SYNDROME OR VELOCARDIOFACIAL SYNDROME Failure of development of the 3 rd and 4 th pharyngeal pouches. Characterised by absence of parathyroid glands and the thymus. T-cell deficiency due to deletion of chromosome 22q11.2. Loss of T-cell mediated immunity. Tetany. Congenital defects of heart and great vessels. Abnormal facies with defects in mouth and ears. Development of recurrent fungal and viral infections.

105. autoimmunity

106. autoimmunity Tolerance to self antigens is an important fundamental property of immune system The breakdown of tolerance is the basis of autoimmune diseases.

107. Types of autoimmune diseases Organ or cell specific autoantibodies Hashimoto’s thyroiditis Pernicious anemia Addison’s disease Pemphigus Pemphigoid ITP Autoimmune hemolytic anemia Myasthenia gravis Non-organ specific autoantibodies Lupus erythematosus Rheumatoid arthritis Sjogrens syndrome Systemic sclerosis Primary biliary cirrhosis Dermatomyositis Mixed connective tissue diseases

108. SYSTEMIC LUPUS ERYTHEMATOSUS Multisystem autoimmune inflammatory disorder of unknown etiology. Important feature is the formation of antibody to DNA. Prevalence is approximately in united states is 1 in 2000 Gender predilection ,women to man ratio is 9:1 Clinical manifestations : Lupus is a great mimic Can virtually affect any organ Skin is affected in upto 85% of SLE patients. Skin lesions of lupus can be classified into lupus- specific and nonspecific.

109. Three types of lupus specific lesions are -acute -subacute -chronic Acute cutaneous lupus occurs in 30 %- 50% of patients Classically represented by the butterfly rash Mask shaped erythematous Bullous lupus and localized erythematous papules also belong to acute lupus category.

110. Chronic cutaneous lupus occurs in 15 % -20% of cases. Affects the skin of the face or scalp in about 80% of cases. The least common subtype,subacute cutaneous lupus, occurs in 10% -15% of patients. Includes papulosquamous and annular- polycyclic eruptions usually on the trunk and arms Nonspecific skin manifestations alopecia photosensitivity raynauds phenomenon livedo reticularis(mottled discoloration due to spasm of underlying vessels)

111. ORAL MANIFESTATIONS Affected in significant percentage of patients. Predominant types of oral lesions being ulcerations,erythematous lesions,and discoid lesions. Occur with increased frequency on the palate and in the oropharynx Are characteristically painless Discoid oral lesions are similar to those occurring on the skin. Appear as whitish striae frequently radiating from the central erythematous area Giving a so called brush border Atrophy and telangiectasias are frequently present

112. Oral manifestations

113. Buccal mucosa ,gingiva, and labial mucosa are the most commonly affected intraoral sites. Direct immunofluorescent staining for immunoglobulins and complement C3 factor is useful to aid in diagnosis. Granular deposition of IgM,IgG , and C3 along the basement membrane is characteristic.

114. LABORATORY FINDINGS : Anemia,leukopenia,and thrombocytopenia are among the most common manifestations of SLE. Anemia of chronic disease is the predominant type. Leukopenia occurs in 50% of the cases. Autoimmune thrombocytopenia is also common and may be severe. Elevation in ESR with normal C- reactive protein levels is characteristric of SLE. Over 100 different autoantibody types are associated with SLE. Best studied are directed against Various nuclear components and phospholipids.

115. ANAs are present in 98% of the SLE patients. Most sensitive diagnostic test for this disease. However ,ANA may be non-specific Being present in many other autoimmune diseases Is present in low titres in upto 1/3 rd of normal population. Anti-double –stranded DNA(anti-ds DNA) antibodies are highly specific. Present in 50-60% of SLE patients. Other antibodies highly specific for SLE but found in a relatively small percentage of patients. Are antiribosomal P ,anti-Smith antigen,and anti ribonucleoprotein

116. Various autoantibody patterns are associated with distinct clinical presentations of SLE. Anti –Ro antibody is linked to subacute cutaneous lupus and neonatal heart block. Antiribososmal P antibodies to lupus psychosis and nephritis. DIAGNOSIS Diagnosis is based on the compatible symptoms and signs in the presence of suggestive laboratory abnormalities. A standardised set of classification criteria,last modified in 2013, were proposed by the Systemic Lupus International Collaborating clinics (SLICC) group.

117. SJOGRENS SYNDROME It is an autoimmune disease characterized by destruction of lacrimal glands and salivary glands. More commonly seen in females. It can be primary when it is called as sicca syndrome. It may be also secondary to other autoimmune disorders. Rheumatoid arthritis being the most commonly associated with the disorder. Presence of anti-ribonucleoprotein antibodies like SS-A(Ro) and SS-B (La). The former is associated with early disease onset,longer disease duration and extraglandular manifestations,such as cutaneous vasculitis and nephritis.

118. Clinical findings

119. Clinical features include xerostomia and keratoconjuctivitis sicca. Mickulicz syndrome include lacrimal and salivary gland enlargement of whatever cause. Patients with sjogrens syndrome has increased risk of developing lymphoid malignancies. MIXED CONNECTIVE TISSUE DISEASE(MCDT) It is a disease seen in a group of patients who are identified clinically with a coexistence of features suggestive of SLE,polymyositis,rheumatoid arthritis,and systemic sclerosis. These patients have high titers of antibodies to RNP (ribonucleoprotein particle) containing U1 RNP

120. SCLERODERMA It is an autoimmune disorder characterized by fibroblast stimulation and collagen deposition in the skin and internal organs. Skin is most commonly affected. Gastrointestinal tract,kidneys,heart,muscles,and lungs also are frequently involved. More commonly seen in the females. Due to release of growth factors acting on the fibroblasts like FGF,PDGF,cytokines like IL-1.

121. Categories of scleroderma Diffuse scleroderma Presence of anti-DNA topoisomerase antibodies( Scl ) Widespread skin involvement Rapid progression Early visceral involvement Symptoms include dysphagia,malabsorption,arrhythmia,renal insufficiency. Limited scleroderma Presence of anti-centromere antibodies Skin involvement confined to finger,forearms and face Visceral involvement occurs late Clinical course is relatively benign Some people develop CREST syndrome

122. Oral manifestations. The reduced mouth opening and fixation of jaw due to involvement of the peri temporomandibular joint tissues Lips become thin,rigid and partially fixed producing microstomia Tongue often becomes stiff and board like, causing the patient difficulty in eating and speaking Gingival tissues are pale and unusually firm Pathological changes in the minor salivary glands.

123. Radiographic features Extreme widening of the pdl space. Two to four times the normal thickness. This may be so striking ,once the association is recognized,may be sufficient for tentative diagnosis of systemic sclerosis. Bone resorption of the angle of the mandibular ramus,usually bilaterally. Partial or complete resorption of condyles and/ or coronoid processes.

124. ACQUIRED IMMUNODEFICIENCY SYNDROME(AIDS) Retroviral disease caused by HIV Characterised by the triad of immunosuppression associated with opportunistic infections secondary neoplasms neurological manifestations Major routes of HIV infection are: Sexual contact-most common mode of spread of infection Parenteral inoculation-includes Intravenous drug abusers Vertical transmission

125. symptoms

126. Parenteral inoculation-includes intravenous drug abusers( the largest group) patients receiving blood and blood components needle stick injury (risk of transmission 0.3 %) The transmission through the parenteral route can be prevented with screening of the blood and taking precautions Vertical transmission-from infected mother to newborn Takes place via transplacental spread infected birth canal( most common route),ingestion of breast milk,

127. Etiology and pathogenesis HIV is a retrovirus belonging to lentivirus family It is of two types-HIV-1 and HIV-2 There are two strains of HIV Macrophage trophic(R5) strain:infects both monocytes/macrophages and T cells. T-cell trophic (X4 virus) strain:it infects only activated T cells P24 is the most readily detected viral antigen and is the target for antibodies used to diagnose HIV infection in blood screening.

128. The commonest cause of AIDS in india is HIV-1 group M subtype C. Almost 90 % of HIV infections are initially transmitted by R5 strains. However,during course of infection ,X4 viruses replace R5 strains due to mutation in genes that encode gp120. Two major targets of HIV infection are the immune system and CNS. The profound immunodeficiency is the hallmark of AIDS. The commonly affected CD4 cells in human body include helper T cells (worst affected),monocyte-macrophages and dendritic cells Defective CCR5 receptors lead to protective effect of providing resistance to the development of AIDS.

129. NATURAL HISTORY OF HIV Acute retroviral syndrome Seen for 3-12 weeks Characterised by high levels of plasma viremia With widespread seeding of the lymphoid tissues Clinically there is a self –limited acute illness with nonspecific symptoms. Symptoms include sore throat,myalgias,fever , rash ,weight loss , fatigue,cervical lymphadenopathy,diarrhea,and vomiting. Macrophages are mainly affected.

130. The middle chronic phase Characterised by a period of clinical latency. Lasting for an average duration of 10 years. There is a continuous battle between the virus and the host immune cells. The immune system is intact,but there is continuous HIV replication. Predominantly in the lymphoid tissues,which may last for several years. Patients are either asymptomatic or develop persistent generalized lymphadenopathy. Th1 cells are mostly affected.

131. The final phase or the stage of crisis Associated with the loss of host immune cells in the battle. And progression to AIDS. It is characterized by the patient presenting with a long –lasting fever (>1 month), fatigue,weight loss and diarrhea. The weight loss is so severe that AIDS is also known as “ Slim’s disease” Opportunistic infections Bacterial infections M. tuberculosis nocardiosis salmonella atypical mycobacterial infection

132. Viral infections: Cytomegalovirus varicella zoster virus Herpes simplex virus Fungal infection: candidiasis histoplasmosis Pneumomycocystis jiroveci coccidiomycosis Cryptococcosis Protozoal infections: Cryptosporidium isosporidium toxoplasmosis

133. NEOPLASMS IN AIDS Kaposi’s sarcoma-most common cancer seen in patients having AIDS. Lymphomas-AIDS related lymphomas include Systemic lymphomas-having CNS as the most common extranodal site for the development of lymphoma Primary CNS lymphoma found more commonly in AIDS than in general population Body cavity lymphomas present as pleural,peritoneal or pericardial effusions Genital cancers-cancer of the cervix and anal cancers due to infection of HPV.

134. WINDOW PERIOD The term used for initial 2-4 weeks When the patient is infectious and the screening test is negative. During which the investigation of HIV is made using polymerase chain reaction for detection of viral nucleic acids. DIAGNOSIS ELISA:used for the detection of antibodies against viral proteins,most sensitive and the best screening test for the diagnosis of AIDS. Western blot-is the most specific or the confirmatory test for HIV. Direct detection of the viral infection is with p24 antigen capture assay,reverse transcriptase –PCR,DNA-PCR and culture of virus from the monocytes and CD4+ T cells.

135. Some important terms. CD4 count : most clinically useful laboratory indicator of degree of immune suppression and is used ,together with clinical staging,in decisions to start ART and prophylaxis against opportunistic infections,and in DD of clinical problems. Normal CD4 count is >500 cells/mm3 ; <200 cells/mm3 -there is severe immune suppression. Viral load :the level of viremia is measured by quantitative PCR of HIV-RNA. Important for monitoring responses to ART and has some prognostic value before starting ART. People with high viral load >100000 copies/ml experience more rapid decline in CD4 count,while those with low viral loads <1000 copies /ml usually have slow or even no decline in CD4 counts.

136. Oral manifestations Recurrent apthous ulcers Herpetiform ulcers Pseudomembranous candidiasis Angular chelitis Herpetic gingivostomatitis NUG Oral hairy leukoplakia Kaposi sarcoma NUP

137. Oral manifestations

138. Autoimmune diseases of oral cavity

139. AUTOIMMUNE DISEASES OF OROFACIAL REGION

140. IMMUNOSURVEILLANCE Immune system keeps a constant check on the malignant cells and kills them on spot. Its called as IMMUNOSURVEILLANCE. Inefficiency of immunosurveillance results in increased incidences of cancers.

141. References Immunology of oral diseases by THOMAS LEHNER 3 rd ed. Burket’s oral medicine 12 th ed. Cawson’s essentials of oral pathology &medicine 8 th ed. Robins 9 th ed Harrison 6 th ed. Immunology by roilt 6 th ed Ananthanarayan 7 th ed. Harsh mohan 5 th ed Immunology by SK GUPTA 1 st ed. Davidson’s medicine 22 nd ed.

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