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The innate immune system

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The innate immune system Powered By Docstoc
					FUNCTIONS AND DYSFUNCTIONS OF THE IMMUNE
                   ►


    SYSTEM WITH EMPHASIS ON THE CNS
     Normal functions and disorders of the immune
                        system

►   Normal functions
      Immunity against microorganisms and pathogens
      Wound healing
      Tumor surveillance
►   Disorders from immune dysfunction
        Autoimmunity
        Immune mediated disorders
        Bystander damage
        Graft rejection
                      The immune system

►   The innate immune system       ►   Adaptive immune system
      Skin                             Antibodies
                                           ► Recognize free antigen
                                           ► Fab and Fc
      Phagocytes
                                        B cells
        ► PMNS
                                           ► Antigen binding stimulates B
        ► Monocytes                          cell proliferation
        ► Macrophages                      ► Most B cells express MHC II
                                           ► Function also as APC
                                        T cells
      Natural killer (NK) cells           ► Promote B cell maturation and
                                             Ab prouction
                                           ► Produce cytokines to enhance
      Acute phase reactants
                                             innate immune system
                                        Antigen presenting cells
      Compliment system
Components of the immune system
                    Components of the immune system


►   Monocytes and macrophages
      4% of the peripheral blood leukocytes
      Contain many enzymes for
          ►   Killing
          ►   Processing antigens
      Monocytes differentiate into tissue specific macrophages

►   Natural killer cells
        2% of peripheral blood leukocytes
        Synonymous with large granular lymphocytes
        Lack immunological memory
        Kill viral infected cells and tumor cells
        Do not need MHC for normal function
     
►   NK1+T cells
      Express both TCR and NK1.1 receptors
         Components of the immune system

►T   lymphocytes
  Originate from the thymus
  Has unique specificity for recognizing antigens
  Generally classified into two groups
      ►CD4+   involved in DTH and B-cell differentiation
      ►CD8+ involved in class 1 restricted lysis of antigen-
       specific targets
  T cells with suppressor activity can express both
   CD4 or CD8
       Components of the immune system

►T   cell receptors
  Are composed of alpha and betha glyocsylated
   polypeptide chains
  Each chain is composed of V ,J and C regions
   resembling Igs
  There are about 100 TCR –variable genes
  T cells can only recognize short peptides associated with
   MHC
  They also express non polymorphic antigens on their
   surface
      ► The   most abundant of which is CD45
         Components of the immune system

►B   LYMPOCYTES
  Are precursors of antibody secreting cells
  Cells develop in the bone marrow
  Contain specific Ig receptor that commit them to
   recognize specific antigen
  They commonly express IgM on their surface but switch
   to other isotypes with the help of T cells
  Following antigenic challenge T cells help B cells
     ► Cognate interaction
     ► Non cognate interaction
              Components of the immune system

►   Immunoglobulin
     Are glycoprotein that are the secretory product of the plasma cells
        ►   Are composed of two light chains and two heavy chains
        ►   According to the chemical nature of the heavy chain they are divided into
               A, G, M ,D and E
        ►   React with peptides , proteins ,lipids
►   Each heavy and light chain are composed of
               Constant region – carboxy terminal (Fc portion)
                  ► Fc portion binds to the host tissue and fixing compliment


               Variable region –amino terminal and form Fab portion

        ►   Immunoglobulin are important for
               Antibody dependant cells-mediated cytotoxicity
               For compliment mediated cell lysis
        ►   Not all immunoglobulin fix complement
               IgM ,IgG1 and IgG3
               Genetics of the immune system

►   Diversity of antigen receptors        ►   MHC/HLA
      Due diversity of V,(D) and J            Distinguish self from non self
       gene segments                           Present antigen to the
                                                appropriate cells
      Recombination inaccuracies at           MHC class I
       the joining sites of the V,D and           ► Alpha chain of MHC gene
       J regions                                  ► small Beta chain non MHC
                                                    gene
      Somatic mutation of B cells                ► HLA-A , HLA-B and HLA-C
       after antigen binding                      ► Regulates specificity of cytotoix
         ►   This phenomenon does not               T cells
             occur in T cells                  MHC class II
                                                  ►   Alpha
                                                  ►   Betha
                                                  ►   HLA –DP , DQ and DR
                                                  ►   Regulates specificity of T helper
                                                      cells
           Organization of the immune response

►   Initiation of the immune response
     Antigen presentation
     Accessory molecules for T cell activation
     Costimulatory molecules
►   Regulation of the immune response
     Cytokines
     Chemokines
►   Termination of the immune response
     B cell inhibition
     Immunoglobulin
     T cells
            Initiation of the immune response

►   Antigen presentation
        monocytes macrophages
        B cells
        Dendrite cells
        Glial cells
►   Accessory molecules for T cell activation
      Involved in recognition, activation, intracellular signaling ,adhesion and trafficing
      CD3
         ► It is part of the TCR complex
         ► Primarily involved in signaling for T cell activation and proliferation through
           ITAM
      CD4 and CD8
         ► Plays an accessory role in signaling and antigen recognition
         ► CD4 binds with the non polymorphic portion of beta MHC II
               Non T cells that expressCD4 : microglial cells and macrophages
         ► CD8 binds with the non polymorphic portion of alpha MHC I
      CD19 found in B cells
                Initiation of the immune response

►   Costimulatory molecules

      B7- CD28 , CD40 - CD154
        ► B7- CD28 secrete IL2 and express Bcl-x anti- apoptotic molecule
        ► CTLA-4 homologous of CD28 and it inhibit T cell activatiion


      The integrin family : VCAM-1 ,ICAM-1, LFA-1 , CD45 and CD2
        ► Also mediate T cell adhesion and guides cell trafficking


      L-selctin , matrix metalloprotinase (MMP) and CD44
         ► Homing receptor
         ► facilitates T cell entry into target peripheral lymphoid organ
                                 Cytokines

 Growth factors
    ► IL-1   IL-2 IL-3 IL-4 and colony stimulating factors
 Activation factors
    ► Interferon   alpha, beta and gamma
 Regulatory or cytotoxic factors
    ► IL-10,   IL-12 ,TGF-B and TNF-alpha
 Are necessary for T cell activation , amplification and modulation
  of immune response
         T helper 1 cells
            ► secret INF-gamma, IL-2 and TNF –alpha

         T helper 2 cells
            ► IL-4 IL-3 IL-6 IL-10 and IL-13

         T 3 cells
            ► TGF beta
                       Chemokines

 Aid in leukocytes directed mobility

 Two families
    ► C-C   FAMILY :MCP MIP-1, RANTES
    ► C-X-C FAMILY: IL-8
 They are produced by immune and non immune cells

 Monocytes , T cells , basophils and eosinophils express receptors for
  chemokines

 CCR5 CXCR4 act as coreceptor for HIV
         Regulation of the immune response

►   Termination of the immune response
     B cell inhibition
        ► Clearance of antigen by the reticuloendothelial system or through the formation
          antigen-antibody complex
        ► Binding of the Ag –Ab complex with Fc receptor on to the CD32 of B cells
          results in the inhibition of B-cell differentiation
     Immunoglobulin
        ►   Anti-idiotypic response to the variable region of the Ig and TCR
     T cells
        ► Anergy
        ► Deletion
        ► Suppressor cell activity
                             Self-Tolerance

►   Central tolerance
      Positive selection
         ► On the cortex of thymus
         ► T cells with no affinity to MHC will die of lack of signal
           activation
         ► Those with MHC survive and become single positive
           thymocyts
      Negative selection
         ► In the thymus medulla
         ► Those cells that display a high affinity to self antigen are
           deleted by apoptosis
                           Self Tolerance

►   Peripheral tolerance
      Anergy
          ► Signal one = APC with its peptide + MHC
               In the absence of signal one cell die of neglect

         ► Signaltwo = co stimulatory signals
              In the absence of signal two T cells become anergic
              Expression of alternate co stimulatory molecule by
               activated T cells CTLA- 4
              IT occur when antigen is presented by non professional
               APC
                               Self-Tolerance

►   Peripheral Tolerance
     Apoptosis
        ► Programmed cell death
        ► Signals of apoptosis
               Withdrawal of growth factor or cytokines
               Exposure to corticosteroids or repeated antigen contact
        ►   Mediatiors of apoptosis
               Anti apoptotic genes = Bcl family of genes
               Proapoptotic genes = Fas family of genes
                  ► Activated T cells express Fas-ligand and Fas
               Activation induced cell death
        ►   Cytokines
               IL-2 , TNF –alpha , INF-gamma
                                  Self-Tolerance

►   Suppressor T cells
      Dawn regulate CD4 or CD8 cells
      T suppressor cells can be
         ► CD4/8
         ► Are antigen specific
      Mediate suppression
         ►   through the production of modulating cytokines
                Th2
                TGF –beta
         ►   expression of negative regulatory molecules
                CTLA-4
    Laboratory Evaluation of Host Defense
                   Status

►   Initial Screening Assays
        ► Complete blood count with differential
        ► smearSerum immunoglobulin levels: IgM, IgG, IgA, IgD, IgE

►   Other Readily Available Assays
      Quantification of blood mononuclear cell populations by
       immunofluorescence assays employing monoclonal antibody
       markersb
        ►  T cells: CD3, CD4, CD8, TCRαβ, TCRγδ
        ► B cells: CD19, CD20, CD21, Ig(µ, δ, γ, α, κ, λ), Ig-associated
          molecules (α, β) Activation markers: HLA-DR, CD25, CD80 (B cells),
          CD154 (T cells)
        ► NK cells: CD16/CD56
             Monocytes: CD15
►   T cell functional evaluation
     1. Delayed hypersensitivity skin tests (PPD, Candida, histoplasmin,
      tetanus toxoid)
     2. Proliferative response to mitogens (anti-CD3 antibody,
      phytohemagglutinin, concanavalin A) and allogeneic cells (mixed
      lymphocyte response)
     3. Cytokine production
►   B cell functional evaluation
      1. Natural or commonly acquired antibodies: isohemagglutinins;
      antibodies to common viruses (influenza, rubella, rubeola) and
      bacterial toxins (diphtheria, tetanus)
     2. Response to immunization with protein (tetanus toxoid) and
      carbohydrate (pneumococcal vaccine, H. influenzae B vaccine)
      antigens
     3. Quantitative IgG subclass determinations
► Complement
   1. CH50 assays (classic and alternative
    pathways)
   2. C3, C4, and other components
► Phagocyte   function
   1. Reduction of nitroblue tetrazolium
   2. Chemotaxis assays
   3. Bactericidal activity
            The Immune system and the CNS

►   The CNS has been termed immune privileged site

     Absence of lymphatic drainage

     BBB

     Low level of MHC factors in the resident cells of the CNS

     Lack of potent antigen presenting cells

     Presence of immunosuppressive factor (TGF-beta)
        Conditions perturbing the immune privilege

►   Entry of inflammatory cells through BBB is facilitated by
      Up regulation of adhesion molecules on endothelial cells
          ►   VCAM
          ►   ICAM
      Activation T cells
►   Enhanced MHC expression by CNS resident cells in the presence of
      Cytokines
      TNF alpha
      IFN gamma
►   Under inflammatory condition
      APCs microgllial cells are the principal
      Secret cytokines
      Express costimulatory molecules
►   High levels of TGF beta and Fas ligand expression dawn regulate the immune
    system in the CNS
      Important in CNS tumor pathogenesis
 Mechanisms Preventing Autoimmunity


► Sequestrationof self-antigen
► Generation and maintenance of tolerance
   a. Central deletion of autoreactive lymphocytes
   b. Peripheral anergy of autoreactive lymphocytes
   c. Receptor replacement by autoreactive
           lymphocytes
► Regulatory   mechanisms
                   Mechanisms of Autoimmunity

►   I. Exogenous
►     A. Molecular mimicry
►     B. Superantigenic stimulation
►     C. Microbial adjuvanticity
►    II. Endogenous
►     A. Altered antigen presentation
►       1. Loss of immunologic privilege
►       2. Presentation of novel or crytic epitopes (epitope spreading)
►       3. Alteration of self-antigen
►       4. Enhanced function of antigen-presenting cells
►        a. Costimulatory molecule expression
►        b. Cytokine production
►     B. Increased T cell help
►       1. Cytokine production
►       2. Costimulatory molecules
►     C. Increased B cell function
►     D. Apoptotic defects
►     E. Cytokine imbalance
►     F. Altered immunoregulation
Human Autoimmune Disease: Presumptive Evidence
       for an Immunologic Pathogenesis


►   Major Criteria
     Presence of autoantibodies or evidence of cellular reactivity to
      self
     Documentation of relevant autoantibody or lymphocytic infiltrate
      in the pathologic lesion.
     Demonstration that relevant autoantibody or T cells can cause
      tissue pathology
         ► a. Transplacental transmission
         ► b. Adaptive transfer into animals
         ► c. In vitro impact on cellular function
►   Supportive Evidence
       Reasonable animal model
       Beneficial effect from immunosuppressive agents
       Association with other evidence of autoimmunity
       No evidence of infection or other obvious cause
                  Autoimmune disease

►   Immune mediated diseases
      Multiple sclerosis
►   Autoimmune diseases
      Classified as
        ►T cell mediated
            MS , CIDP , Polymyositis
        ►B cell mediated
            Lambert-Eaton syndrome
        ►Combination of both
            Myasthenia Gravis
                                     Multiple sclerosis
► Females are affected 2:1
► Is a complex polygenic disease
        Associated with HLA-DR2
► Environment
► Immune system in MS
        Presence of OCB
        Reactivity to various myelin antigens
           ►   Activation of myelin specific-T cells through molecular mimicry or super antigen in the periphery
        Th1 mediated disease
►   Interferon –beta
        Increased production of IL10 by macrophages dawn regulate Th-1cells
        Decrease production of IL-12 by macrophages
        modulate adhesion molecule expression
           ►   Changing cell associated VCAM In to soluble VCAM
        Dawn regulate co stimulatory molecule expression
►   Copaxone
        A synthetic molecule that resemble myelin
        Binds with MHC grove and is believed the T cells to wards these structure are biased toTh2
         cells
             Acute disseminated encephalomyelitis

►   A monophasic demyelinating disease

►   Associated with vaccination or
      Rabies and small pox vaccines which were prepared with neural tissues

      Molecular mimicry is the most likely mechanism


►   systemic viral infection (Parainfectious variant)

      Measles ,rubella , mumps ,and several other viral infections


►   Its pathology closely mimic that of MS
                     Immune mediated neuropathies
►   AIDP
     Pathology
           ►   Perinural infiltration by lymphocytes , monocytes ,and macrophages
           ►   Auto antibodies to GM1, Gd1a , and Gd1b
     It is primarily an antibody mediated disease
           ►   Improvement by plasmapheresis
           ►   Demyelination up on transfer of immunoglobulin to experimental animal
     Occurrence of AIDP has been linked with many infections
           ►   C. jejuni is one of the most commonly identified agent
                    Autoantibodies identified in GBS patients GMI , Gd1a ,Gd1b , and Gq1b
           ►   Herpes , M .pneumonia and many other bacterial and viral infefctions
►   CIDP
     No specific autoantibody has been identified
     Histopathological picture
           ►   is similar with AIDP
           ►    but wit fewer inflammatory cells
           ►   Onion bulb appearance
     Indirect evidence that it is T cell mediated disease
                    Autoimmune Myasthenia Gravis
►   Autoimmune disease
        80-90 % cases have detectable auto antibodies to AChR
        Most cases occur in females
        Thymomas occur in 10- 15 % of patients
        75% of patients will have some thymic abnormality (thymic hyperplasia )
        Hyperplastic thymic cells over express V beta 5.1+TCR T cells
        Often associated with other autoimmune diseases
           ►   Thyroid disorder
           ►   Rheumatoid arthritis
           ►   Pernicious anemia
           ►   SLE
        Auto reactive T cell are necessary for the disease to occur
           ►   Failure of central tolerance may play an important role in disease pathogenesis
           ►   Removal of the thymus results in improvement of disease in 80-90% of patients
        B cells are effectors
►   Genetics
        HLAB8 and DDRw3
►   Rx
        actylchloinesterase inhibitors , IVIG ,plasmapheresis ,corticosteroids
         ,immunosuppressive ,and thymectomy
                           Inflammatory Muscle disease

► PM ,DM , and IBM are immune mediated diseases
► PM
         Is thought to be caused by many causes : systemic autoimmunity , connective tissue disorder
          and viral and bacterial infection
         Pathologically x-ed by
            ►   endomysial CD8 cell infiltrates
            ►   Relative sparing of blood vessels
         Anti jo-1 antibody in upto 30% patients
►   DM
         Perifacicular atrophy secondary to microvascular damage
         Capillary damage is mediated by complement
         Anti jo-1 antibody in upto 30% patients


►   IBM
         Damage is mediated by CD8 T cells
         Autophagic vacuoles
         Amyloid deposites
                      Paraneoplastic Syndromes

►   Mediated by antibodies in reaction to tumor antigen
►   Autoimmune disease


                      Anti-Hu          Anti- Yo     Anti - Ri


           SCC        ENCEPHALOMYELI
                      TIS AND/ OR
                      SENSORY
                      NEUROPATHY

           BREAST                      CEREBELLAR
                                       DEGENERATI
           AND                         ON
           OVARIAN
           BREAST                                   Opsoclonu
           AND                                      s-
           OVARIAN                                  myoclonus
                              Tumor immunology

►   Tumor immunosurveillance
      Prevent or inhibit tumor growth
      The main effectors are : CTLs, NK and TNF-alpha producing macrophges
►   Tumor cells escape surveillance mechanisms by
        Masking or modulating antigens on their surface
        Dawn regulation of classI andII MHC
        Producing immunosuppressant like TGF –beta
        Expressing high level of FasL allowing for local apoptosis
►   Therapeutic strategies
        Vaccination with Tumor cells or antigen
        Transfect tumor cells with plasmids congaing costimulatory molecules
        Injection of tumor cells with cytokines such as IL-2 and TNF –alpha
        Introduction of lymphokine activated cells (LAC)

				
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