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Neuroimmunology

The document provides an overview of the immune system, including its normal functions, divisions, components, cells, molecules, and regulation. The key points are: - The immune system protects against pathogens and prevents reinfection through immunological memory. Its divisions are the innate and adaptive systems. - The innate system provides first response via nonspecific defenses like skin, phagocytes, and natural killer cells. The adaptive system responds antigen-specifically via T and B cells. - T cells recognize antigen via T cell receptors and MHC molecules and mediate cellular immunity. B cells recognize antigen directly and produce antibodies for humoral immunity. - Cytokines mediate communication between immune cells, directing immune responses. Regulatory

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NEURO IMMUNOLOGY Susanth MJ
NORMAL FUNCTIONS OF THE IMMUNE SYSTEM  Protect the organism against infectious agents and prevent reinfection by maintaining immunological memory  Wound healing  Tumor surveillance
FUNCTIONAL DIVISIONS OF IMMUNE SYSTEM Innate Immune System  body's first line of defense against pathogens  acts nonspecifically Adaptive Immune System  secondary, antigen-specific response  mediated by T cells and B cells
COMPONENTS OF INNATE IMMUNE SYSTEM  Skin  Phagocytes  include polymorphonuclear cells, monocytes, and macrophages  Natural killer (NK) cells  Acute-phase proteins - C-reactive protein  Complement system
COMPONENTS OF ADAPTIVE IMMUNE SYSTEM  B cells  T cells or thymus-derived cells  CD4 T cells  CD8 T cells  Antibodies (Immunoglobulins (Igs)  APCs  macrophages, monocytes, dendritic cells, and Langerhans cells.
CELLS OF THE IMMUNE SYSTEM Pluripotent Stem Cells In The Bone Marrow Myeloid Lineage Neutrophils Basophils Eosinophils Macrophages Lymphoid Lineage T Cells B Cells NK Cells
MAJOR HISTOCOMPATIBILITY AND HUMAN LEUKOCYTE ANTIGENS Important function of presenting antigen to the appropriate cells In view of the extensive polymorphisms present, the chances of two unrelated individuals sharing identical HLA antigens are extremely low Serve to distinguish self from nonself
MHC CLASS I ANTIGENS  Expressed on all nucleated cells  Includes HLA-A, B, and C  Regulate the specificity of cytotoxic CD8 + T cells
MHC CLASS II ANTIGENS  Constitutively expressed on dendritic cells, macrophages, and B cells  On activation expressed on T cells, endothelial cells, and astrocytes  Includes HLA-DP, DQ, and DR  Regulate the specificity of CD 4 T-helper cells, which in turn regulate DTH and antibody response to foreign antigens
APCS  required to present antigen to T cells  macrophages, monocytes, dendritic cells, and Langerhans cells  found primarily in the skin, lymph nodes, spleen, and thymus  process antigen intracellularly and present antigen peptide in the groove of their MHC class II molecules
MONOCYTES AND MACROPHAGES  4% of the peripheral blood leukocytes  abundant cytoplasm and a kidney-shaped nucleus  Monocytes differentiate into tissue-specific macrophages including Kupffer cells of the liver and brain microglia
NATURAL KILLER CELLS  2.5% of peripheral blood lymphocytes  Large intracytoplasmic azurophilic granules and high cytoplasm-to-nucleus ratio  Activated primarily in response to interferons  Involved in  Elimination of virally infected host cells  Tumor immunity  Lack immunological memory  Lack the cell surface markers present on B cells and T cells
T LYMPHOCYTES  Originate from the thymus  respond to peptide antigens only CD4 + T cells (T-helper (T H) cells )  expressing CD4 antigen on their cell surface CD8 + T cells (cytotoxic T cells)  expressing CD8 on their surface Suppressor or regulator T cells  Can express either CD4 or CD8. Most abundantly expressed antigen in T cells is CD45
CD4 T CELLS  Recognize antigen presented in association with MHC class II on the surface of APCs  Promote B-cell maturation and antibody production  Produce factors called cytokines to enhance the innate or nonspecific immune response
CD8 T CELLS  Recognize antigen in association with MHC class-I antigen on the surface of most cells  Play an important role in eliminating virus-infected cells  Damaging target cells via the release of degrading enzymes and cytokines
T-CELL RECEPTORS  Heterodimer consisting of two chains stabilized by interchain and intrachain disulfide bonds  Associated with the CD3 antigen to form the TCR complex  Can only recognize short peptides that are associated with MHC molecules
B LYMPHOCYTES Switch to other isotypes, while maintaining antigen specificity ↓ Differentiate and form mature antibody-secreting plasma cells Acquire Ig receptors (normally IgM ) T-cell help Directly (cognate interaction) Indirectly by secreting helper factors (noncognate interaction) Bone marrow Respond to proteins, peptides, polysaccharides, nucleic acids, lipids, and small chemicals
IMMUNOGLOBULINS  Glycoproteins that are the secretory product of plasma cells  Each molecule consists of light chains (kappa [κ] or lambda [λ]) linked to two identical heavy chains  According to heavy chain, Igs divided into five main classes: IgM, IgD, IgG, IgA, and IgE
IMMUNOGLOBULINS  Each heavy and light chain consists of variable and constant regions  Variable unit acts as the antigen- binding site ( Fab portion)  CHO terminal of heavy chain (Fc portion) involved in binding to host tissue and fixing complement  important for antibody-dependent, cell- mediated cytotoxicity and for complement-mediated cell lysis
HOW DIVERSITY ACHIEVED Diversity in variable (V) and joining (J) gene segments of the antigen receptors Affinity Maturation Antigen ↔ B cells ↓ Undergo somatic mutations ↓ Increase the diversity and the affinity of antigen binding This phenomenon does not occur in T cells Isotype switching Recombination of variable region with new constant region genes ↓ Other Ig types 1 2 3
HOW IT WORKS Antigens in the periphery ↓ Lymphatics or blood vessels ↓ Lymph nodes and spleen APCs Monocyte-macrophage lineage and B cells Processed intracellularly Presented not as whole molecules but as highly immunogenic peptides T cells Proliferation Cytokine production
MOLECULES ACTIVE IN IMMUNE PROCESS APCs Site of antigen presentation Chemokines chemoattractant peptides that regulate leukocyte migration Integrins includes VCAM-1, ICAM-1, LFA-3, CD45, and CD2 Mediates adhesion to endothelial cells and guiding cell traffic L-selectins Facilitate the rolling of leucocytes along the surface of endothelial cells Function as a homing receptor to target organs MMPs Proteinases secreted by inflammatory cells digest extracellular matrix, thereby facilitating lymphocyte entry through basement membranes including the blood- brain barrier (BBB) APCs APCs
ACCESSORY MOLECULES FOR T-CELL ACTIVATION CD3  Part of the TCR complex CD4 and CD8 Binds to MHC class II β chain Binds to MHC class I molecule Accessory role in signaling and antigen recognition
COSTIMULATORY MOLECULES “Second signal” to facilitate T-cell activation Stimulatory (positive)  B7-CD28, CD40-CD154 pathways  critical for T-cell activation Inhibitory (negative) signal  B7-CTLA4 and PD1-PD ligand
B-CELL ACTIVATION Activation of transcription factors (c- Fos, JunB, NFκB, and c-Myc) ↓ Promote proliferation and Ig secretion T cell dependent Responding to peptide antigens T cell independent Respond to Nonprotein antigens Cytokines from T- helper Induce isotype switching Stronger and long- lived memory B cells Weak IgM responses
INTERACTION BETWEEN B CELLS AND T-HELPER (CD4 +) CELLS  Requires expression of MHC class II by B cells and is antigen dependent  Occurs in the peripheral lymphoid organs  Generation of high-affinity antibody-producing B cells and memory B cells in the germinal center of lymphoid follicles (Affinity Maturation) B cells T cells B7 ↔ CD28 CD40 ↔ CD154
REGULATION OF THE IMMUNE RESPONSE Cytokines A. Growth factors: IL-1, IL-2, IL-3, and IL-4 and colony-stimulating factors B. Activation factors : Interferons (α, β, and γ, which are also antiviral) C. Regulatory or cytotoxic factors : IL-10, IL-12, TGF- β, Lymphotoxins, and TNF-α D. Chemokines : IL-8, MIP-1α, and MIP-1β
CYTOKINES IL-4 and B-cell differentiation factors Differentiation and expansion of committed B cells to become plasma cells MacrophagesIL-1 T cells IL-2 and IL-2 R •Clonal expansion of T cells •Activation of NK cells •Lysis of tumor cell targets IFN-γ •Induce expression of MHC class I and class II molecules on many cell types including APCs •Increases the T-cell response to the antigen IL-3 Hematopoietic stem cells
CYTOKINES IFN-α and IFN-β  Both type I interferons  IFN-α by macrophages, whereas IFN-β by fibroblasts  Inhibit viral replication  Inhibit the proliferation of lymphocytes
TGF-β  produced by T cells and macrophages  decrease cell proliferation IL-10  Growth factor for B cells  Inhibits the production of IFN-γ  Antiinflammatory effects CYTOKINES
CD4 + T-HELPER CELLS T H3 cells  Secrete TGF-β  Inhibits proliferation of T cells  Inhibits activation of macrophages T H1 cells •IFN-γ, IL-2, and TNF-α •Proinflammatory functions •Mediate diseases such as MS T H2 cells •IL-4, IL-5, IL-6, IL-10, and IL-13 •Promote antibody production by B cells •Enhance eosinophil functions •Suppress cell-mediated immunity (CMI) Cytokines of the T H1 type may inhibit production of T H2 cytokines and vice versa
T H-17 CELLS  Subset of T cells that predominantly produce IL-17  Both T H1 and T H2 cytokines suppress the development of T H17 cells  Facilitate the recruitment of neutrophils and participate in the response to gram-negative organism  May also play a role in the initiation of autoimmune disease
SELF-TOLERANCE  An organism's ability to maintain a state of unresponsiveness to its own antigens  Maintained through three principal mechanisms  Deletion, anergy, and suppression  Categorized as either central or peripheral tolerance Failure lead to autoimmune disorers
SELF-TOLERANCE Central Tolerance In Thymus Positive selection  TCR with no affinity to MHC will fail to receive signals needed for maturation and will die in situ  Low affinity to MHC survive and become MHC I (CD8 +) or MHC II (CD4 +). Negative selection  High affinity toward self-antigen are deleted by apoptosis
SELF-TOLERANCE Peripheral Tolerance  For Self-reactive lymphocytes that escape central tolerance  Maintained through clonal anergy or clonal deletion
TERMINATION OF AN IMMUNE RESPONSE B-Cell Inhibition  Antigen-antibody complexes through binding of the Fc receptor to the CD32 (FcγRIIB) receptor on the surface of the B cell.  Anti-idiotypic responses  Variable regions of the Ig and the TCR can act as antigens (idiotopes)
TERMINATION OF AN IMMUNE RESPONSE T Cell Inhibition a) Anergy or functional unresponsiveness  occurs when there is insufficient T-cell activation b) Apoptosis  Repeated stimulation may lead to activation-induced cell death through c) Suppressor cell activity  Notably by secretion of T H2 and T H3 cytokines
ANERGY DUE TO FAILURE OF T-CELL ACTIVATION A. Absence of signal , T cell dies because of neglect B. Absence of costimulatory signals, the T cell becomes anergic Up-regulates CTLA-4 CD80 and CD86 on the surface of APCs C. Activated T cell
APOPTOSIS  Withdrawal of growth factors  Cytokines  TNF-α and IFN-γ, IL-2  Complete absence of either of these cytokines results in deficient T-cell apoptosis, inability to terminate the immune response, and uncontrolled autoimmune disease  Exposure to corticosteroids  Activation-Induced Cell Death (AICD)
APOPTOSIS Activation-Induced Cell Death (AICD)  Repeated exposure to antigens  Induce apoptosis via the Fas/FasL pathway  Autoreactive T lymphocyte may encounter large doses of self-antigen in the periphery and consequently may be deleted by AICD  Mutations in the Fas gene associated with an autoimmune disease
REGULATORY T CELLS  Can be of the CD4 + or CD8 +subtypes  Down-regulate CD4 and CD8 T-cell responses  action by production of immunosuppressive cytokines (T H2 or TGF-β) or through T-T cell interactions, including the expression of CTLA-4  Important role in the control of the immune response in autoimmune disorders, and the function of regulatory T cells may be enhanced by immunomodulatory therapies.
IMMUNE SYSTEM AND CENTRAL NERVOUS SYSTEM Immunologically privileged site because of  (1) absence of lymphatic drainage, limiting the immunological circulation  (2) blood-brain barrier (BBB), which limits the passage of immune cells and factors  (3) low level of expression of MHC factors, particularly MHC II in the resident cells of the CNS  (4) low levels of potent APCs, such as Dendritic or Langerhans cells  (5) presence of immunosuppressive factors such as TGF-β and CD200
 Because of the lack of a lymphatic system, antigens drain along perivascular spaces  T cells must be activated before crossing the BBB  Entry is facilitated by expression of receptors for adhesion molecules, including α4-integrin.  Neurons express MHC class I only when damaged and in the presence of IFN-γ  Expression of MHC antigens on both microglia and astrocytes are enhanced by the presence of cytokines, TNF-α, and IFN-γ IMMUNE SYSTEM AND CENTRAL NERVOUS SYSTEM
NEUROGLIAL CELLS AND THE IMMUNE RESPONSE Microglia and Astrocytes  Participate in immune responses within the CNS  Central role in initiating and propagating immune- mediated diseases of the CNS
MICROGLIA  derived from bone marrow cells during ontogeny  three principal types of cells: perivascular, parenchymal, and Kolmer cells, in the choroid plexus Activated microglia  express higher levels of MHC class II  produce higher levels of proinflammatory cytokines including TNF-α, IL-6, and IL-1, as well as nitric oxide and glutamate
MICROGLIA  Primary functions are immune surveillance for foreign antigens and phagocytic scavengers of cellular debris  Participate in antigen presentation within the CNS under certain conditions esp perivascular microglia  Role in regulating the programmed elimination of neural cells during brain development  Enhance neuronal survival by producing neurotrophic and antiinflammatory cytokines  Role in neuroregeneration and repair
MICROGLIA Overactivation of microglia, possibly by microbes or other environmental factors ↓ Chronic proinflammatory milieu in the CNS ↓ Progressive neurodegeneration.  Deleterious role in several neurodegenerative diseases: MS, ALS, Parkinson disease and HIV-associated dementia  Strategies to down-regulate such responses are under investigation
ASTROCYTES  role in the glia limitans at the BBB  physical support of neuronal and axonal structures an provision of growth factors  secrete cytokines including TGF-β  critical role in converting glutamate to glutamine ( less glutamate-mediated neurotoxicity)  produce stromal-derived factor-1 (SDF-1) - significant role in HIV-associated dementia
REGULATION OF IMMUNITY IN CNS  TGF-β produced by astrocytes and microglia down- regulating immune responses locally  TGF-β by Neurons facilitate the differentiation of regulatory T cells  Increased expression of Fas ligand in the CNS compared with PNS may increase apoptosis of T cells
REGULATION OF IMMUNITY IN CNS  Neurons expressing CD200 inhibit activation of microglia and macrophages  Neurons expressing Fractalkine (CXCL1)  Down-regulate microglial-mediated neurotoxicity ( Parkinson disease and ALS )  Increase NK cells play (inhibitory role in CNS inflammation esp in MS)
IS BRAIN AN IMMUNOLOGICALLY SEQUESTERED ORGAN ? Cells of the CNS not only respond to inflammatory stimuli but are also capable of producing cytokines and other inflammatory factors, often directly under the influence of lymphocytes and is closely involved with the systemic immune response
NEURO AUTOIMMUNE DISEASE Results as a culmination of interactions between genetic predisposition, environmental factors, and failure of self-tolerance maintenance mechanisms B-cell mediated diseases  autoantigen present  MG - antibodies to the α subunit of the acetylcholine receptor  LES - antibodies targeting calcium channels T cell–mediated diseases  Little evidence for autoantigen  MS, inflammatory demyelinating polyneuropathy, and polymyositis
GENETIC FACTORS IN AUTOIMMUNE DISEASES  Association between certain MHC haplotypes and disease  MS - HLA-DR2 allele  MG - HLA-DR3  Association may be due to the ability of a particular MHC molecule to bind and present autoantigen to the T cell  Disease linkage tends to be more with class II genes, suggesting a key role for T-cell autoimmunity.  Many autoimmune diseases are more frequent in females (estrogen's effects on the immune system )
ENVIRONMENTAL FACTORS IN AUTOIMMUNE DISEASES Molecular mimicry  environmental antigen resembling a self-antigen elicits an immune response to both itself and the self-antigen  Streptococcal-induced chorea, Gd1b axonal neuropathy, Semple rabies vaccine-induced encephalomyelitis, and the anti-Hu paraneoplastic syndrome  MS - remote infection with EBV(epitopes of EBV resemble MBP)
ENVIRONMENTAL FACTORS IN AUTOIMMUNE DISEASES Epitope spreading Once an inflammatory reaction proceeds ↓ Tissue injury expose other self-antigens that were previously unrecognized by the immune system ↓ For unknown reasons, peripheral tolerance mechanisms fail, and an autoimmune reaction ensues ↓ Perpetuating immune-mediated reactions and causing chronic diseases
ENVIRONMENTAL FACTORS IN AUTOIMMUNE DISEASES Therapies that inhibit molecular mimicry or epitope spreading may be useful in preventing autoimmune diseases
MULTIPLE SCLEROSIS  Increased incidence with  HLA-DR2 (DR1501) haplotype  single nucleotide polymorphism of IL-2R and IL-7R alleles  Inverse association between sunlight exposure and MS  active form of vitamin D, calcitriol down-regulate proinflammatory dendritic cells (DC) and reduce T H1 lymphocyte responses while promoting antiinflammatory T H2 lymphocyte responses
MULTIPLE SCLEROSIS  No clear autoantigen  Immune-mediated disease rather than an autoimmune disease  Cell-mediated immunity, primarily involving T-helper cells, is believed to play an important role in initiating the disease  Oligoclonal bands are commonly observed; however, the target of these antibodies has yet to be elucidated  Activated microglia are found in progressive forms of the disease and have been associated with axonal damage and demyelination
IMMUNOPATHOGENESIS OF MS Activation of MBP-reactive T cells predominantly T H1 via molecular mimicry or by a superantigen presumably in the periphery ↓ VCAM-1 and its ligand, VLA-4 Cross the BBB Reactivated T cells in the CNS Perivascular dendritic-like cells have been shown to play a role ↓ IL-2, IFN-γ, NO and TNF-α ↓ Myelin damage Induce B-cell activation and antibody production that further damage myelin
IMMUNO PHARMACOTHERAPY OF MS Activation of periperal T cells ↓ VCAM-1 and its ligand, VLA-4 Cross the BBB ↓ Reactivated T cells in the CNS ↓ IL-2, IFN-γ, NO and TNF-α ↓ Myelin damage B-cell activation β-Interferon (IFN-β) •↑ IL-10 by macrophages •↓ IL-12 by dendritic cells •modulates adhesion molecule expression •↓ costimulatory molecule expression
IMMUNO PHARMACOTHERAPY OF MS Activation of periperal T cells ↓ VCAM-1 and its ligand, VLA-4 Cross the BBB ↓ Reactivated T cells in the CNS ↓ IL-2, IFN-γ, NO and TNF-α ↓ Myelin damage B-cell activation Glatiramer acetate (GA) •bind with high affinity to the MHC groove, leading to the generation of GA-specific T cells •display a T H2 bias •down-regulation of the immune responses
IMMUNO PHARMACOTHERAPY OF MS Activation of periperal T cells ↓ VCAM-1 Cross the BBB ↓ Reactivated T cells in the CNS ↓ IL-2, IFN-γ, NO and TNF-α ↓ Myelin damage Campath-1H (Phase 2 studies) •targets CD52 receptor present on lymphocytes and monocytes •depletion of peripheral lymphocytes Daclizumab •blocks the IL-2R α chain (CD25) on T cells •inhibits T-cell replication
IMMUNO PHARMACOTHERAPY OF MS Activation of periperal T cells ↓ VCAM-1 Cross the BBB ↓ Reactivated T cells in the CNS ↓ IL-2, IFN-γ, NO and TNF-α ↓ Myelin damage CTLA4 Ig •blocks B7-CD28 costimulatory signals on T cells •induce T-cell anergy in vivo Fingolimod •Targets sphingosine-1- phosphate receptor, which is necessary for lymphocyte egress from lymph nodes
IMMUNO PHARMACOTHERAPY OF MS Activation of periperal T cells ↓ VCAM-1 and its ligand, VLA-4 Cross the BBB ↓ Reactivated T cells in the CNS ↓ IL-2, IFN-γ, NO and TNF-α ↓ Myelin damage Natalizumab VLA-4 (α4β1-integrin) antibody B-cell activation Rituximab antibody that primarily targets activated B cells
Nonspecific strategies  Cyclophosphamide, Mitoxantrone, and Cladribine  depress bone marrow production of cells, including T cells Cyclophosphamide  inducing a cytokine switch, with a decrease in IL-12 and an increase in IL-4, IL-5, and TGF-β IMMUNO PHARMACOTHERAPY OF MS
NEUROMYELITIS OPTICA (NMO), OR DEVIC DISEASE  antibodies targeting the aquaporin-4 water channel present on the surface of the glia limitans at the BBB  Rituximab is effective
ACUTE DISSEMINATED ENCEPHALOMYELITIS  Viral or bacterial epitopes resembling myelin antigens activate myelin-reactive T-cell clones through molecular mimicry  30% has serum antibodies to MOG, which were absent in MS patients  Oligoclonal bands may very rarely be present, and these cases should be followed for the development of MS
IMMUNE-MEDIATED NEUROPATHIES - AIDP OR GBS  Incidence of infection has been reported to be 90% in the 30 days before occurrence  high incidence with C. jejuni infections  autoantibodies to myelin glycolipids, including GM1, GD1a, and GD1b  Miller-Fisher variant of GBS - GQ1b antibodies  Antibody-mediated demyelination due to complement fixation  axonal damage - result of bystander damage
IMMUNE-MEDIATED NEUROPATHIES - CIDP  no specific autoantibodies  fewer inflammatory infiltrates  mixed demyelination and axonal changes  indirect evidence that CIDP is T-cell mediated; however, this area is still under investigation
TREATMENT OF IMMUNE-MEDIATED NEUROPATHIES Plasmapheresis  short-term immunotherapy that nonspecifically removes antibodies from the circulation IVIG  immunomodulating agent  works in part through the presence of Fc fragments that interact with the inhibitory Fc receptor, FcγRIIB, which is also induced on macrophages following IVIG administration  displace low-affinity autoantibodies from the nerve
TREATMENT OF IMMUNE-MEDIATED NEUROPATHIES High-dose steroids  not effective in AIDP.  CIDP responds well Immunosuppressants such as cyclosporine A, cyclophosphamide, and azathioprine  In refractory cases of CIDP  Future therapies for AIDP or CIDP may target complement activation or inhibition of axonal calpain activation.
AUTOIMMUNE MYASTHENIA GRAVIS  80% to 90% - autoantibodies to the α subunit of the acetylcholine receptor (AChR)  Thymomas occur in 10% to 15% of cases; most are in the older age group  75% of patients will have a thymic abnormality, 85% being thymic hyperplasia  patients with thymomas have antibodies to additional skeletal muscle proteins such as the ryanodine receptor and titin, as well as the neuromuscular junctional protein, MuSK
AUTOIMMUNE MYASTHENIA GRAVIS Both B & T cell–mediated disease  Antibodies Polyclonal and may be of any IGg subtype  Poor correlation between serum antibody titers and disease course and severity.  Failure of central or thymic tolerance may play an important role  Autoreactive T cells are necessary for the disease to occur
THERAPIES IN MG Thymectomy  recommended for patients 15 to 65 years old, with 80% to 90% remission rate Plasmapheresis and IVIG for acute MG exacerbations or in preparation for surgery Cyclosporine, Azathioprine, and Mycophenolate  Augment treatment when symptoms are not adequately controlled
THERAPIES IN MG Corticosteroids  used at various stages of treatment  multiple effects on the immune system, including reducing AChR antibody levels. Investigational therapies  Target specific molecules such as the B-cell surface Ig or the TCR  Immunotoxins
INFLAMMATORY MUSCLE DISEASES PM  a/w systemic autoimmune connective-tissue disorders and viral and bacterial infections  endomysial inflammatory infiltrate containing predominantly CD8 + T cells DM  characterized by perifascicular atrophy  Antibody-mediated disease IBM  mediated by CD8 + T cells
AUTOANTIBODIES IN INFLAMMATORY MUSCLE DISEASES  Various autoantibodies directed against nuclear and cytoplasmic cell components in up to 30%  Viruses including coxsackie B are implicated in the pathogenesis  PM and DM patients may have anti-Jo-1 antibodies to the viral enzyme, histidyl-tRNA synthetase
THERAPY OF INFLAMMATORY MUSCLE DISEASES Corticosteroids  mainstay of treatment of PM and DM  IBM may be more resistant  IVIG, methotrexate, azathioprine, cyclophosphamide, cyclosporine  Alternative treatment options Total lymphoid or whole-body irradiation  In extreme cases
NEURODEGENERATIVE DISEASE & IMMUNITY - AD  Amyloid plaque clearance by either microglial- and complement-mediated clearance or through direct antibody-amyloid interactions  Immunization with amyloid-β peptide → amyloid-β- specific antibodies, which enhanced the clearance of amyloid plaques  patients developed meningoencephalitis, due to T-cell responses to amyloid-β  Induction of an antibody and microglial-mediated clearance of amyloid in the absence of a prominent T H1 response is the current goal of therapy
NEURODEGENERATIVE DISEASE & IMMUNITY - ALS  Activated microglia in areas of severe motor neuron loss  Minocycline, which acts in part by inhibiting microglial activation, has shown some initial promise in the treatment of ALS
IMMUNE RESPONSE TO INFECTIOUS DISEASES  Balance the need to eliminate the pathogen and the risk of inducing bystander damage to the delicate and vital nervous tissues ↓  Many pathogens are not completely eliminated and may persist to cause further symptoms. CNS syphilis, Lyme neuroborreliosis, herpes zoster, HIV, and Mycobacterium tuberculosis
IMMUNE RESPONSE TO INFECTIOUS DISEASES Viral meningitis  Portal of entry is mucosal membrane, usually the nasopharynx  Strong local immune response  By the time the virus disseminates to the leptomeninges, a sufficient immune response has been mounted in the periphery to eliminate the pathogen Viral encephalitis •CNS invasion is so sudden •Peripheral immune system has insufficient time to react, and the weak cns immune response is often inadequate, resulting in a poor outcome Portal of entry and site of replication of the pathogen plays a critical role
HIV-ASSOCIATED DEMENTIA (HAD)  CD4 is the cell surface receptor for HIV and microglia and macrophages can express low levels of CD4  may explain the propensity of HIV for CNS  HIV protein, gp120, can bind directly to CXCR4 on neurons, resulting in neuronal signaling and apoptosis  Glial-mediated neurotoxicity plays a significant role in the pathogenesis  production of neurotoxic factors and proinflammatory cytokines by HIV-infected microglia and astrocytes
TUMOR IMMUNOLOGY  Tumor immunosurveillance to prevent the formation of tumors or inhibit further growth  Main effector cells are CTLs, NK cells, and TNF-α- producing macrophages  Tumor cells escape surveillance mechanisms by  Masking or modulating antigens on their surface  Down-regulating class I and II molecules  Expressing immunosuppressant factors.  Increased frequencies of regulatory T cells
IMMUNOTHERAPY IN TUMOURS Therapies to exploit the body's natural tumor immunosurveillance mechanisms Daclizumab (Anti-CD25 Antibody)  Reduces regulatory T-cell function and enhanced host tumor immunity  Vaccination with killed tumor cells or tumor antigens
IMMUNOTHERAPY IN TUMOURS  Therapies to exploit the body's natural tumor immunosurveillance mechanisms  Genetic engineering to transfect tumors with plasmids bearing genes for costimulatory molecules to enhance the tumor APC ability  Injection of cytokines such as IL-2 and tnf-α, which enhance lymphocyte and NK function  Dendritic cells pulsed with tumor antigens to induce NK cell-mediated tumor killing esp in CNS gliomas
PARANEOPLASTIC SYNDROMES  Neurological syndromes arising in association with a distant cancer  Mediated by antibodies produced by the immune system in reaction to a tumor antigen, which cross- react with neural tissue  Cancers associated with paraneoplastic syndromes are generally associated with a better outcome
Antibodies Associated malignancy Paraneoplastic Syndrome Anti-Hu antibody Small-cell cancer of the lung Encephalomyelitis and/or sensory neuropathy Anti-Yo antibody Breast and ovarian cancer Cerebellar degeneration Anti-Ri antibody breast and ovarian cancer Opsoclonus-myoclonus syndrome Antibodies against VGKC Acquired neuromyotonia, or Isaac syndrome Morvan syndrome, characterized by neuromyotonia and insomnia
Antibodies Associated malignancy Paraneoplastic Syndrome Antibodies against the P/Q type of voltage-gated calcium channels Small-cell cancer of the lung Lambert-Eaton myasthenic syndrome Antibodies to glutamic acid decarboxylase (GAD) Breast cancer Stiff person syndrome
ANTIBODY-ASSOCIATED NEUROLOGICAL SYNDROMES Antiphospholipid (APL) syndrome, or Hughes syndrome  Chorea, strokes, bleeding, migraine headaches, and epilepsy CNS lupus  Antibodies directed against the NR2A and NR2B subunits of the NMDA receptor in some Rasmussen encephalitis  Antibodies directed against glutamate receptor 3 (GluR3)  form of severe intractable epilepsy localized to one hemisphere and partially responsive to immunotherapy
ANTIBODY-ASSOCIATED NEUROLOGICAL SYNDROMES Molecular mimicry mechanisms related to streptococcal infections  Sydenham chorea  Tourette syndrome  Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infection (PANDAS), which encompasses tics and obsessive-compulsive disorder in children
IMMUNOLOGY OF CNS TRANSPLANT  Tend to have longer survival times than peripheral grafts  Major factor in the survival is their lack of immunogenicity in the relatively immune-privileged site of the CNS
FACTORS THAT INFLUENCE CNS GRAFT SURVIVAL  Type of graft (xenogenic, allogeneic, genetically modified tissue, or stem cell populations)  Location of the graft, with the periventricular areas being the most susceptible to rejection  Presence of antigen-presenting cells within the graft, which can be eliminated in purified grafts  Host immunosuppression
NEURAL STEM CELLS (NSCS)  Suppress disease through immunomodulatory mechanisms in MS  can directly inhibit T-cell proliferation in response to concanavalin A (ConA) or to MOG peptide by inducing T-cell apoptosis; or through nitric oxide– and PGE2- mediated T-cell suppression  Can express costimulatory molecules, CD80 and CD86, particularly after exposure to the proinflammatory cytokines, IFN-γ and TNF-α
SUMMARY  Field of immunology has progressed significantly in the past 30 years  Can expect many advances in the field of neuroimmunology, including new therapies and better strategies for the treatment of neurological diseases
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Neuroimmunology

  • 1.
  • 2.
    NORMAL FUNCTIONS OFTHE IMMUNE SYSTEM  Protect the organism against infectious agents and prevent reinfection by maintaining immunological memory  Wound healing  Tumor surveillance
  • 3.
    FUNCTIONAL DIVISIONS OFIMMUNE SYSTEM Innate Immune System  body's first line of defense against pathogens  acts nonspecifically Adaptive Immune System  secondary, antigen-specific response  mediated by T cells and B cells
  • 4.
    COMPONENTS OF INNATEIMMUNE SYSTEM  Skin  Phagocytes  include polymorphonuclear cells, monocytes, and macrophages  Natural killer (NK) cells  Acute-phase proteins - C-reactive protein  Complement system
  • 5.
    COMPONENTS OF ADAPTIVEIMMUNE SYSTEM  B cells  T cells or thymus-derived cells  CD4 T cells  CD8 T cells  Antibodies (Immunoglobulins (Igs)  APCs  macrophages, monocytes, dendritic cells, and Langerhans cells.
  • 6.
    CELLS OF THEIMMUNE SYSTEM Pluripotent Stem Cells In The Bone Marrow Myeloid Lineage Neutrophils Basophils Eosinophils Macrophages Lymphoid Lineage T Cells B Cells NK Cells
  • 7.
    MAJOR HISTOCOMPATIBILITY ANDHUMAN LEUKOCYTE ANTIGENS Important function of presenting antigen to the appropriate cells In view of the extensive polymorphisms present, the chances of two unrelated individuals sharing identical HLA antigens are extremely low Serve to distinguish self from nonself
  • 8.
    MHC CLASS IANTIGENS  Expressed on all nucleated cells  Includes HLA-A, B, and C  Regulate the specificity of cytotoxic CD8 + T cells
  • 9.
    MHC CLASS IIANTIGENS  Constitutively expressed on dendritic cells, macrophages, and B cells  On activation expressed on T cells, endothelial cells, and astrocytes  Includes HLA-DP, DQ, and DR  Regulate the specificity of CD 4 T-helper cells, which in turn regulate DTH and antibody response to foreign antigens
  • 10.
    APCS  required topresent antigen to T cells  macrophages, monocytes, dendritic cells, and Langerhans cells  found primarily in the skin, lymph nodes, spleen, and thymus  process antigen intracellularly and present antigen peptide in the groove of their MHC class II molecules
  • 11.
    MONOCYTES AND MACROPHAGES 4% of the peripheral blood leukocytes  abundant cytoplasm and a kidney-shaped nucleus  Monocytes differentiate into tissue-specific macrophages including Kupffer cells of the liver and brain microglia
  • 12.
    NATURAL KILLER CELLS 2.5% of peripheral blood lymphocytes  Large intracytoplasmic azurophilic granules and high cytoplasm-to-nucleus ratio  Activated primarily in response to interferons  Involved in  Elimination of virally infected host cells  Tumor immunity  Lack immunological memory  Lack the cell surface markers present on B cells and T cells
  • 13.
    T LYMPHOCYTES  Originatefrom the thymus  respond to peptide antigens only CD4 + T cells (T-helper (T H) cells )  expressing CD4 antigen on their cell surface CD8 + T cells (cytotoxic T cells)  expressing CD8 on their surface Suppressor or regulator T cells  Can express either CD4 or CD8. Most abundantly expressed antigen in T cells is CD45
  • 14.
    CD4 T CELLS Recognize antigen presented in association with MHC class II on the surface of APCs  Promote B-cell maturation and antibody production  Produce factors called cytokines to enhance the innate or nonspecific immune response
  • 15.
    CD8 T CELLS Recognize antigen in association with MHC class-I antigen on the surface of most cells  Play an important role in eliminating virus-infected cells  Damaging target cells via the release of degrading enzymes and cytokines
  • 16.
    T-CELL RECEPTORS  Heterodimerconsisting of two chains stabilized by interchain and intrachain disulfide bonds  Associated with the CD3 antigen to form the TCR complex  Can only recognize short peptides that are associated with MHC molecules
  • 17.
    B LYMPHOCYTES Switch toother isotypes, while maintaining antigen specificity ↓ Differentiate and form mature antibody-secreting plasma cells Acquire Ig receptors (normally IgM ) T-cell help Directly (cognate interaction) Indirectly by secreting helper factors (noncognate interaction) Bone marrow Respond to proteins, peptides, polysaccharides, nucleic acids, lipids, and small chemicals
  • 18.
    IMMUNOGLOBULINS  Glycoproteins thatare the secretory product of plasma cells  Each molecule consists of light chains (kappa [κ] or lambda [λ]) linked to two identical heavy chains  According to heavy chain, Igs divided into five main classes: IgM, IgD, IgG, IgA, and IgE
  • 19.
    IMMUNOGLOBULINS  Each heavyand light chain consists of variable and constant regions  Variable unit acts as the antigen- binding site ( Fab portion)  CHO terminal of heavy chain (Fc portion) involved in binding to host tissue and fixing complement  important for antibody-dependent, cell- mediated cytotoxicity and for complement-mediated cell lysis
  • 20.
    HOW DIVERSITY ACHIEVED Diversityin variable (V) and joining (J) gene segments of the antigen receptors Affinity Maturation Antigen ↔ B cells ↓ Undergo somatic mutations ↓ Increase the diversity and the affinity of antigen binding This phenomenon does not occur in T cells Isotype switching Recombination of variable region with new constant region genes ↓ Other Ig types 1 2 3
  • 21.
    HOW IT WORKS Antigensin the periphery ↓ Lymphatics or blood vessels ↓ Lymph nodes and spleen APCs Monocyte-macrophage lineage and B cells Processed intracellularly Presented not as whole molecules but as highly immunogenic peptides T cells Proliferation Cytokine production
  • 22.
    MOLECULES ACTIVE INIMMUNE PROCESS APCs Site of antigen presentation Chemokines chemoattractant peptides that regulate leukocyte migration Integrins includes VCAM-1, ICAM-1, LFA-3, CD45, and CD2 Mediates adhesion to endothelial cells and guiding cell traffic L-selectins Facilitate the rolling of leucocytes along the surface of endothelial cells Function as a homing receptor to target organs MMPs Proteinases secreted by inflammatory cells digest extracellular matrix, thereby facilitating lymphocyte entry through basement membranes including the blood- brain barrier (BBB) APCs APCs
  • 23.
    ACCESSORY MOLECULES FORT-CELL ACTIVATION CD3  Part of the TCR complex CD4 and CD8 Binds to MHC class II β chain Binds to MHC class I molecule Accessory role in signaling and antigen recognition
  • 24.
    COSTIMULATORY MOLECULES “Second signal”to facilitate T-cell activation Stimulatory (positive)  B7-CD28, CD40-CD154 pathways  critical for T-cell activation Inhibitory (negative) signal  B7-CTLA4 and PD1-PD ligand
  • 25.
    B-CELL ACTIVATION Activation oftranscription factors (c- Fos, JunB, NFκB, and c-Myc) ↓ Promote proliferation and Ig secretion T cell dependent Responding to peptide antigens T cell independent Respond to Nonprotein antigens Cytokines from T- helper Induce isotype switching Stronger and long- lived memory B cells Weak IgM responses
  • 26.
    INTERACTION BETWEEN BCELLS AND T-HELPER (CD4 +) CELLS  Requires expression of MHC class II by B cells and is antigen dependent  Occurs in the peripheral lymphoid organs  Generation of high-affinity antibody-producing B cells and memory B cells in the germinal center of lymphoid follicles (Affinity Maturation) B cells T cells B7 ↔ CD28 CD40 ↔ CD154
  • 27.
    REGULATION OF THEIMMUNE RESPONSE Cytokines A. Growth factors: IL-1, IL-2, IL-3, and IL-4 and colony-stimulating factors B. Activation factors : Interferons (α, β, and γ, which are also antiviral) C. Regulatory or cytotoxic factors : IL-10, IL-12, TGF- β, Lymphotoxins, and TNF-α D. Chemokines : IL-8, MIP-1α, and MIP-1β
  • 28.
    CYTOKINES IL-4 and B-celldifferentiation factors Differentiation and expansion of committed B cells to become plasma cells MacrophagesIL-1 T cells IL-2 and IL-2 R •Clonal expansion of T cells •Activation of NK cells •Lysis of tumor cell targets IFN-γ •Induce expression of MHC class I and class II molecules on many cell types including APCs •Increases the T-cell response to the antigen IL-3 Hematopoietic stem cells
  • 29.
    CYTOKINES IFN-α and IFN-β Both type I interferons  IFN-α by macrophages, whereas IFN-β by fibroblasts  Inhibit viral replication  Inhibit the proliferation of lymphocytes
  • 30.
    TGF-β  produced byT cells and macrophages  decrease cell proliferation IL-10  Growth factor for B cells  Inhibits the production of IFN-γ  Antiinflammatory effects CYTOKINES
  • 31.
    CD4 + T-HELPERCELLS T H3 cells  Secrete TGF-β  Inhibits proliferation of T cells  Inhibits activation of macrophages T H1 cells •IFN-γ, IL-2, and TNF-α •Proinflammatory functions •Mediate diseases such as MS T H2 cells •IL-4, IL-5, IL-6, IL-10, and IL-13 •Promote antibody production by B cells •Enhance eosinophil functions •Suppress cell-mediated immunity (CMI) Cytokines of the T H1 type may inhibit production of T H2 cytokines and vice versa
  • 32.
    T H-17 CELLS Subset of T cells that predominantly produce IL-17  Both T H1 and T H2 cytokines suppress the development of T H17 cells  Facilitate the recruitment of neutrophils and participate in the response to gram-negative organism  May also play a role in the initiation of autoimmune disease
  • 33.
    SELF-TOLERANCE  An organism'sability to maintain a state of unresponsiveness to its own antigens  Maintained through three principal mechanisms  Deletion, anergy, and suppression  Categorized as either central or peripheral tolerance Failure lead to autoimmune disorers
  • 34.
    SELF-TOLERANCE Central Tolerance In Thymus Positiveselection  TCR with no affinity to MHC will fail to receive signals needed for maturation and will die in situ  Low affinity to MHC survive and become MHC I (CD8 +) or MHC II (CD4 +). Negative selection  High affinity toward self-antigen are deleted by apoptosis
  • 35.
    SELF-TOLERANCE Peripheral Tolerance  ForSelf-reactive lymphocytes that escape central tolerance  Maintained through clonal anergy or clonal deletion
  • 36.
    TERMINATION OF ANIMMUNE RESPONSE B-Cell Inhibition  Antigen-antibody complexes through binding of the Fc receptor to the CD32 (FcγRIIB) receptor on the surface of the B cell.  Anti-idiotypic responses  Variable regions of the Ig and the TCR can act as antigens (idiotopes)
  • 37.
    TERMINATION OF ANIMMUNE RESPONSE T Cell Inhibition a) Anergy or functional unresponsiveness  occurs when there is insufficient T-cell activation b) Apoptosis  Repeated stimulation may lead to activation-induced cell death through c) Suppressor cell activity  Notably by secretion of T H2 and T H3 cytokines
  • 38.
    ANERGY DUE TOFAILURE OF T-CELL ACTIVATION A. Absence of signal , T cell dies because of neglect B. Absence of costimulatory signals, the T cell becomes anergic Up-regulates CTLA-4 CD80 and CD86 on the surface of APCs C. Activated T cell
  • 39.
    APOPTOSIS  Withdrawal ofgrowth factors  Cytokines  TNF-α and IFN-γ, IL-2  Complete absence of either of these cytokines results in deficient T-cell apoptosis, inability to terminate the immune response, and uncontrolled autoimmune disease  Exposure to corticosteroids  Activation-Induced Cell Death (AICD)
  • 40.
    APOPTOSIS Activation-Induced Cell Death(AICD)  Repeated exposure to antigens  Induce apoptosis via the Fas/FasL pathway  Autoreactive T lymphocyte may encounter large doses of self-antigen in the periphery and consequently may be deleted by AICD  Mutations in the Fas gene associated with an autoimmune disease
  • 41.
    REGULATORY T CELLS Can be of the CD4 + or CD8 +subtypes  Down-regulate CD4 and CD8 T-cell responses  action by production of immunosuppressive cytokines (T H2 or TGF-β) or through T-T cell interactions, including the expression of CTLA-4  Important role in the control of the immune response in autoimmune disorders, and the function of regulatory T cells may be enhanced by immunomodulatory therapies.
  • 42.
    IMMUNE SYSTEM ANDCENTRAL NERVOUS SYSTEM Immunologically privileged site because of  (1) absence of lymphatic drainage, limiting the immunological circulation  (2) blood-brain barrier (BBB), which limits the passage of immune cells and factors  (3) low level of expression of MHC factors, particularly MHC II in the resident cells of the CNS  (4) low levels of potent APCs, such as Dendritic or Langerhans cells  (5) presence of immunosuppressive factors such as TGF-β and CD200
  • 43.
     Because ofthe lack of a lymphatic system, antigens drain along perivascular spaces  T cells must be activated before crossing the BBB  Entry is facilitated by expression of receptors for adhesion molecules, including α4-integrin.  Neurons express MHC class I only when damaged and in the presence of IFN-γ  Expression of MHC antigens on both microglia and astrocytes are enhanced by the presence of cytokines, TNF-α, and IFN-γ IMMUNE SYSTEM AND CENTRAL NERVOUS SYSTEM
  • 44.
    NEUROGLIAL CELLS ANDTHE IMMUNE RESPONSE Microglia and Astrocytes  Participate in immune responses within the CNS  Central role in initiating and propagating immune- mediated diseases of the CNS
  • 45.
    MICROGLIA  derived frombone marrow cells during ontogeny  three principal types of cells: perivascular, parenchymal, and Kolmer cells, in the choroid plexus Activated microglia  express higher levels of MHC class II  produce higher levels of proinflammatory cytokines including TNF-α, IL-6, and IL-1, as well as nitric oxide and glutamate
  • 46.
    MICROGLIA  Primary functionsare immune surveillance for foreign antigens and phagocytic scavengers of cellular debris  Participate in antigen presentation within the CNS under certain conditions esp perivascular microglia  Role in regulating the programmed elimination of neural cells during brain development  Enhance neuronal survival by producing neurotrophic and antiinflammatory cytokines  Role in neuroregeneration and repair
  • 47.
    MICROGLIA Overactivation of microglia,possibly by microbes or other environmental factors ↓ Chronic proinflammatory milieu in the CNS ↓ Progressive neurodegeneration.  Deleterious role in several neurodegenerative diseases: MS, ALS, Parkinson disease and HIV-associated dementia  Strategies to down-regulate such responses are under investigation
  • 48.
    ASTROCYTES  role inthe glia limitans at the BBB  physical support of neuronal and axonal structures an provision of growth factors  secrete cytokines including TGF-β  critical role in converting glutamate to glutamine ( less glutamate-mediated neurotoxicity)  produce stromal-derived factor-1 (SDF-1) - significant role in HIV-associated dementia
  • 49.
    REGULATION OF IMMUNITYIN CNS  TGF-β produced by astrocytes and microglia down- regulating immune responses locally  TGF-β by Neurons facilitate the differentiation of regulatory T cells  Increased expression of Fas ligand in the CNS compared with PNS may increase apoptosis of T cells
  • 50.
    REGULATION OF IMMUNITYIN CNS  Neurons expressing CD200 inhibit activation of microglia and macrophages  Neurons expressing Fractalkine (CXCL1)  Down-regulate microglial-mediated neurotoxicity ( Parkinson disease and ALS )  Increase NK cells play (inhibitory role in CNS inflammation esp in MS)
  • 51.
    IS BRAIN ANIMMUNOLOGICALLY SEQUESTERED ORGAN ? Cells of the CNS not only respond to inflammatory stimuli but are also capable of producing cytokines and other inflammatory factors, often directly under the influence of lymphocytes and is closely involved with the systemic immune response
  • 52.
    NEURO AUTOIMMUNE DISEASE Resultsas a culmination of interactions between genetic predisposition, environmental factors, and failure of self-tolerance maintenance mechanisms B-cell mediated diseases  autoantigen present  MG - antibodies to the α subunit of the acetylcholine receptor  LES - antibodies targeting calcium channels T cell–mediated diseases  Little evidence for autoantigen  MS, inflammatory demyelinating polyneuropathy, and polymyositis
  • 53.
    GENETIC FACTORS INAUTOIMMUNE DISEASES  Association between certain MHC haplotypes and disease  MS - HLA-DR2 allele  MG - HLA-DR3  Association may be due to the ability of a particular MHC molecule to bind and present autoantigen to the T cell  Disease linkage tends to be more with class II genes, suggesting a key role for T-cell autoimmunity.  Many autoimmune diseases are more frequent in females (estrogen's effects on the immune system )
  • 54.
    ENVIRONMENTAL FACTORS INAUTOIMMUNE DISEASES Molecular mimicry  environmental antigen resembling a self-antigen elicits an immune response to both itself and the self-antigen  Streptococcal-induced chorea, Gd1b axonal neuropathy, Semple rabies vaccine-induced encephalomyelitis, and the anti-Hu paraneoplastic syndrome  MS - remote infection with EBV(epitopes of EBV resemble MBP)
  • 55.
    ENVIRONMENTAL FACTORS INAUTOIMMUNE DISEASES Epitope spreading Once an inflammatory reaction proceeds ↓ Tissue injury expose other self-antigens that were previously unrecognized by the immune system ↓ For unknown reasons, peripheral tolerance mechanisms fail, and an autoimmune reaction ensues ↓ Perpetuating immune-mediated reactions and causing chronic diseases
  • 56.
    ENVIRONMENTAL FACTORS INAUTOIMMUNE DISEASES Therapies that inhibit molecular mimicry or epitope spreading may be useful in preventing autoimmune diseases
  • 57.
    MULTIPLE SCLEROSIS  Increasedincidence with  HLA-DR2 (DR1501) haplotype  single nucleotide polymorphism of IL-2R and IL-7R alleles  Inverse association between sunlight exposure and MS  active form of vitamin D, calcitriol down-regulate proinflammatory dendritic cells (DC) and reduce T H1 lymphocyte responses while promoting antiinflammatory T H2 lymphocyte responses
  • 58.
    MULTIPLE SCLEROSIS  Noclear autoantigen  Immune-mediated disease rather than an autoimmune disease  Cell-mediated immunity, primarily involving T-helper cells, is believed to play an important role in initiating the disease  Oligoclonal bands are commonly observed; however, the target of these antibodies has yet to be elucidated  Activated microglia are found in progressive forms of the disease and have been associated with axonal damage and demyelination
  • 59.
    IMMUNOPATHOGENESIS OF MS Activationof MBP-reactive T cells predominantly T H1 via molecular mimicry or by a superantigen presumably in the periphery ↓ VCAM-1 and its ligand, VLA-4 Cross the BBB Reactivated T cells in the CNS Perivascular dendritic-like cells have been shown to play a role ↓ IL-2, IFN-γ, NO and TNF-α ↓ Myelin damage Induce B-cell activation and antibody production that further damage myelin
  • 60.
    IMMUNO PHARMACOTHERAPY OFMS Activation of periperal T cells ↓ VCAM-1 and its ligand, VLA-4 Cross the BBB ↓ Reactivated T cells in the CNS ↓ IL-2, IFN-γ, NO and TNF-α ↓ Myelin damage B-cell activation β-Interferon (IFN-β) •↑ IL-10 by macrophages •↓ IL-12 by dendritic cells •modulates adhesion molecule expression •↓ costimulatory molecule expression
  • 61.
    IMMUNO PHARMACOTHERAPY OFMS Activation of periperal T cells ↓ VCAM-1 and its ligand, VLA-4 Cross the BBB ↓ Reactivated T cells in the CNS ↓ IL-2, IFN-γ, NO and TNF-α ↓ Myelin damage B-cell activation Glatiramer acetate (GA) •bind with high affinity to the MHC groove, leading to the generation of GA-specific T cells •display a T H2 bias •down-regulation of the immune responses
  • 62.
    IMMUNO PHARMACOTHERAPY OFMS Activation of periperal T cells ↓ VCAM-1 Cross the BBB ↓ Reactivated T cells in the CNS ↓ IL-2, IFN-γ, NO and TNF-α ↓ Myelin damage Campath-1H (Phase 2 studies) •targets CD52 receptor present on lymphocytes and monocytes •depletion of peripheral lymphocytes Daclizumab •blocks the IL-2R α chain (CD25) on T cells •inhibits T-cell replication
  • 63.
    IMMUNO PHARMACOTHERAPY OFMS Activation of periperal T cells ↓ VCAM-1 Cross the BBB ↓ Reactivated T cells in the CNS ↓ IL-2, IFN-γ, NO and TNF-α ↓ Myelin damage CTLA4 Ig •blocks B7-CD28 costimulatory signals on T cells •induce T-cell anergy in vivo Fingolimod •Targets sphingosine-1- phosphate receptor, which is necessary for lymphocyte egress from lymph nodes
  • 64.
    IMMUNO PHARMACOTHERAPY OFMS Activation of periperal T cells ↓ VCAM-1 and its ligand, VLA-4 Cross the BBB ↓ Reactivated T cells in the CNS ↓ IL-2, IFN-γ, NO and TNF-α ↓ Myelin damage Natalizumab VLA-4 (α4β1-integrin) antibody B-cell activation Rituximab antibody that primarily targets activated B cells
  • 65.
    Nonspecific strategies  Cyclophosphamide,Mitoxantrone, and Cladribine  depress bone marrow production of cells, including T cells Cyclophosphamide  inducing a cytokine switch, with a decrease in IL-12 and an increase in IL-4, IL-5, and TGF-β IMMUNO PHARMACOTHERAPY OF MS
  • 66.
    NEUROMYELITIS OPTICA (NMO),OR DEVIC DISEASE  antibodies targeting the aquaporin-4 water channel present on the surface of the glia limitans at the BBB  Rituximab is effective
  • 67.
    ACUTE DISSEMINATED ENCEPHALOMYELITIS Viral or bacterial epitopes resembling myelin antigens activate myelin-reactive T-cell clones through molecular mimicry  30% has serum antibodies to MOG, which were absent in MS patients  Oligoclonal bands may very rarely be present, and these cases should be followed for the development of MS
  • 68.
    IMMUNE-MEDIATED NEUROPATHIES -AIDP OR GBS  Incidence of infection has been reported to be 90% in the 30 days before occurrence  high incidence with C. jejuni infections  autoantibodies to myelin glycolipids, including GM1, GD1a, and GD1b  Miller-Fisher variant of GBS - GQ1b antibodies  Antibody-mediated demyelination due to complement fixation  axonal damage - result of bystander damage
  • 69.
    IMMUNE-MEDIATED NEUROPATHIES -CIDP  no specific autoantibodies  fewer inflammatory infiltrates  mixed demyelination and axonal changes  indirect evidence that CIDP is T-cell mediated; however, this area is still under investigation
  • 70.
    TREATMENT OF IMMUNE-MEDIATED NEUROPATHIES Plasmapheresis short-term immunotherapy that nonspecifically removes antibodies from the circulation IVIG  immunomodulating agent  works in part through the presence of Fc fragments that interact with the inhibitory Fc receptor, FcγRIIB, which is also induced on macrophages following IVIG administration  displace low-affinity autoantibodies from the nerve
  • 71.
    TREATMENT OF IMMUNE-MEDIATED NEUROPATHIES High-dosesteroids  not effective in AIDP.  CIDP responds well Immunosuppressants such as cyclosporine A, cyclophosphamide, and azathioprine  In refractory cases of CIDP  Future therapies for AIDP or CIDP may target complement activation or inhibition of axonal calpain activation.
  • 72.
    AUTOIMMUNE MYASTHENIA GRAVIS 80% to 90% - autoantibodies to the α subunit of the acetylcholine receptor (AChR)  Thymomas occur in 10% to 15% of cases; most are in the older age group  75% of patients will have a thymic abnormality, 85% being thymic hyperplasia  patients with thymomas have antibodies to additional skeletal muscle proteins such as the ryanodine receptor and titin, as well as the neuromuscular junctional protein, MuSK
  • 73.
    AUTOIMMUNE MYASTHENIA GRAVIS BothB & T cell–mediated disease  Antibodies Polyclonal and may be of any IGg subtype  Poor correlation between serum antibody titers and disease course and severity.  Failure of central or thymic tolerance may play an important role  Autoreactive T cells are necessary for the disease to occur
  • 74.
    THERAPIES IN MG Thymectomy recommended for patients 15 to 65 years old, with 80% to 90% remission rate Plasmapheresis and IVIG for acute MG exacerbations or in preparation for surgery Cyclosporine, Azathioprine, and Mycophenolate  Augment treatment when symptoms are not adequately controlled
  • 75.
    THERAPIES IN MG Corticosteroids used at various stages of treatment  multiple effects on the immune system, including reducing AChR antibody levels. Investigational therapies  Target specific molecules such as the B-cell surface Ig or the TCR  Immunotoxins
  • 76.
    INFLAMMATORY MUSCLE DISEASES PM a/w systemic autoimmune connective-tissue disorders and viral and bacterial infections  endomysial inflammatory infiltrate containing predominantly CD8 + T cells DM  characterized by perifascicular atrophy  Antibody-mediated disease IBM  mediated by CD8 + T cells
  • 77.
    AUTOANTIBODIES IN INFLAMMATORYMUSCLE DISEASES  Various autoantibodies directed against nuclear and cytoplasmic cell components in up to 30%  Viruses including coxsackie B are implicated in the pathogenesis  PM and DM patients may have anti-Jo-1 antibodies to the viral enzyme, histidyl-tRNA synthetase
  • 78.
    THERAPY OF INFLAMMATORYMUSCLE DISEASES Corticosteroids  mainstay of treatment of PM and DM  IBM may be more resistant  IVIG, methotrexate, azathioprine, cyclophosphamide, cyclosporine  Alternative treatment options Total lymphoid or whole-body irradiation  In extreme cases
  • 79.
    NEURODEGENERATIVE DISEASE &IMMUNITY - AD  Amyloid plaque clearance by either microglial- and complement-mediated clearance or through direct antibody-amyloid interactions  Immunization with amyloid-β peptide → amyloid-β- specific antibodies, which enhanced the clearance of amyloid plaques  patients developed meningoencephalitis, due to T-cell responses to amyloid-β  Induction of an antibody and microglial-mediated clearance of amyloid in the absence of a prominent T H1 response is the current goal of therapy
  • 80.
    NEURODEGENERATIVE DISEASE &IMMUNITY - ALS  Activated microglia in areas of severe motor neuron loss  Minocycline, which acts in part by inhibiting microglial activation, has shown some initial promise in the treatment of ALS
  • 81.
    IMMUNE RESPONSE TOINFECTIOUS DISEASES  Balance the need to eliminate the pathogen and the risk of inducing bystander damage to the delicate and vital nervous tissues ↓  Many pathogens are not completely eliminated and may persist to cause further symptoms. CNS syphilis, Lyme neuroborreliosis, herpes zoster, HIV, and Mycobacterium tuberculosis
  • 82.
    IMMUNE RESPONSE TOINFECTIOUS DISEASES Viral meningitis  Portal of entry is mucosal membrane, usually the nasopharynx  Strong local immune response  By the time the virus disseminates to the leptomeninges, a sufficient immune response has been mounted in the periphery to eliminate the pathogen Viral encephalitis •CNS invasion is so sudden •Peripheral immune system has insufficient time to react, and the weak cns immune response is often inadequate, resulting in a poor outcome Portal of entry and site of replication of the pathogen plays a critical role
  • 83.
    HIV-ASSOCIATED DEMENTIA (HAD) CD4 is the cell surface receptor for HIV and microglia and macrophages can express low levels of CD4  may explain the propensity of HIV for CNS  HIV protein, gp120, can bind directly to CXCR4 on neurons, resulting in neuronal signaling and apoptosis  Glial-mediated neurotoxicity plays a significant role in the pathogenesis  production of neurotoxic factors and proinflammatory cytokines by HIV-infected microglia and astrocytes
  • 84.
    TUMOR IMMUNOLOGY  Tumorimmunosurveillance to prevent the formation of tumors or inhibit further growth  Main effector cells are CTLs, NK cells, and TNF-α- producing macrophages  Tumor cells escape surveillance mechanisms by  Masking or modulating antigens on their surface  Down-regulating class I and II molecules  Expressing immunosuppressant factors.  Increased frequencies of regulatory T cells
  • 85.
    IMMUNOTHERAPY IN TUMOURS Therapiesto exploit the body's natural tumor immunosurveillance mechanisms Daclizumab (Anti-CD25 Antibody)  Reduces regulatory T-cell function and enhanced host tumor immunity  Vaccination with killed tumor cells or tumor antigens
  • 86.
    IMMUNOTHERAPY IN TUMOURS Therapies to exploit the body's natural tumor immunosurveillance mechanisms  Genetic engineering to transfect tumors with plasmids bearing genes for costimulatory molecules to enhance the tumor APC ability  Injection of cytokines such as IL-2 and tnf-α, which enhance lymphocyte and NK function  Dendritic cells pulsed with tumor antigens to induce NK cell-mediated tumor killing esp in CNS gliomas
  • 87.
    PARANEOPLASTIC SYNDROMES  Neurologicalsyndromes arising in association with a distant cancer  Mediated by antibodies produced by the immune system in reaction to a tumor antigen, which cross- react with neural tissue  Cancers associated with paraneoplastic syndromes are generally associated with a better outcome
  • 88.
    Antibodies Associated malignancy Paraneoplastic Syndrome Anti-Hu antibody Small-cell cancerof the lung Encephalomyelitis and/or sensory neuropathy Anti-Yo antibody Breast and ovarian cancer Cerebellar degeneration Anti-Ri antibody breast and ovarian cancer Opsoclonus-myoclonus syndrome Antibodies against VGKC Acquired neuromyotonia, or Isaac syndrome Morvan syndrome, characterized by neuromyotonia and insomnia
  • 89.
    Antibodies Associated malignancy Paraneoplastic Syndrome Antibodies against theP/Q type of voltage-gated calcium channels Small-cell cancer of the lung Lambert-Eaton myasthenic syndrome Antibodies to glutamic acid decarboxylase (GAD) Breast cancer Stiff person syndrome
  • 90.
    ANTIBODY-ASSOCIATED NEUROLOGICAL SYNDROMES Antiphospholipid (APL)syndrome, or Hughes syndrome  Chorea, strokes, bleeding, migraine headaches, and epilepsy CNS lupus  Antibodies directed against the NR2A and NR2B subunits of the NMDA receptor in some Rasmussen encephalitis  Antibodies directed against glutamate receptor 3 (GluR3)  form of severe intractable epilepsy localized to one hemisphere and partially responsive to immunotherapy
  • 91.
    ANTIBODY-ASSOCIATED NEUROLOGICAL SYNDROMES Molecular mimicrymechanisms related to streptococcal infections  Sydenham chorea  Tourette syndrome  Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infection (PANDAS), which encompasses tics and obsessive-compulsive disorder in children
  • 92.
    IMMUNOLOGY OF CNSTRANSPLANT  Tend to have longer survival times than peripheral grafts  Major factor in the survival is their lack of immunogenicity in the relatively immune-privileged site of the CNS
  • 93.
    FACTORS THAT INFLUENCECNS GRAFT SURVIVAL  Type of graft (xenogenic, allogeneic, genetically modified tissue, or stem cell populations)  Location of the graft, with the periventricular areas being the most susceptible to rejection  Presence of antigen-presenting cells within the graft, which can be eliminated in purified grafts  Host immunosuppression
  • 94.
    NEURAL STEM CELLS(NSCS)  Suppress disease through immunomodulatory mechanisms in MS  can directly inhibit T-cell proliferation in response to concanavalin A (ConA) or to MOG peptide by inducing T-cell apoptosis; or through nitric oxide– and PGE2- mediated T-cell suppression  Can express costimulatory molecules, CD80 and CD86, particularly after exposure to the proinflammatory cytokines, IFN-γ and TNF-α
  • 95.
    SUMMARY  Field ofimmunology has progressed significantly in the past 30 years  Can expect many advances in the field of neuroimmunology, including new therapies and better strategies for the treatment of neurological diseases
  • 96.