FUNCTIONS AND DYSFUNCTIONS OF THE IMMUNE SYSTEM WITH EMPHASIS ON THE CNS

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FUNCTIONS AND DYSFUNCTIONS OF THE IMMUNE
SYSTEM WITH EMPHASIS ON THE CNS

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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

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The immune system

• The innate immune system
• Skin
• Phagocytes
• PMNS
• Monocytes
• Macrophages
• Natural killer (NK) cells
• Acute phase reactants
• Compliment system

• Adaptive immune system
• Antibodies
• Recognize free antigen
• Fab and Fc
• B cells
• Antigen binding stimulates B cell proliferation
• Most B cells express MHC II
• Function also as APC
• T cells
• Promote B cell maturation and Ab prouction
• Produce cytokines to enhance innate immune system
• Antigen presenting cells

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Components of the immune system
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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
• NK1T cells
• Express both TCR and NK1.1 receptors

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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

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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

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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

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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

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Genetics of the immune system

• Diversity of antigen receptors
• Due diversity of V,(D) and J gene segments
• Recombination inaccuracies at the joining sites
  of the V,D and J regions
• Somatic mutation of B cells after antigen binding
• This phenomenon does not occur in T cells

• MHC/HLA
• Distinguish self from non self
• Present antigen to the appropriate cells
• MHC class I
• Alpha chain of MHC gene
• small Beta chain non MHC gene
• HLA-A , HLA-B and HLA-C
• Regulates specificity of cytotoix T cells
• MHC class II
• Alpha
• Betha
• HLA DP , DQ and DR
• Regulates specificity of T helper cells

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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

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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

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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

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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

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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

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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

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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

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Self Tolerance

• Peripheral tolerance
• Anergy
• Signal one APC with its peptide MHC
• In the absence of signal one cell die of neglect
• Signal two 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

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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

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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

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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, TCRaß, TCR?d  
• B cells  CD19, CD20, CD21, Ig(µ, d, ?, a, ?, ?),
  Ig-associated molecules (a, ß)  Activation
  markers HLA-DR, CD25, CD80 (B cells), CD154 (T
  cells) 
•  NK cells  CD16/CD56  
• Monocytes  CD15

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• 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

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• 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

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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)

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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

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Mechanisms Preventing Autoimmunity

• Sequestration of 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

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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

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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

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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

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Multiple sclerosis

• Females are affected 21
• 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

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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

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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

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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
  5.1TCR 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

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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

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Paraneoplastic Syndromes

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

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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)