neuroimmunology

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

PluripotentStem 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 WORKSAntigens 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 chainBinds 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 Igsecretion

T cell dependent

Responding to peptide

antigens

T cell independent

Respond to Nonprotein

antigensCytokines 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)


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


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


Cross the BBB

↓


↓


↓

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




Cross the BBB

↓


↓


↓

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



↓ VCAM-1

Cross the BBB

↓


↓


↓

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



↓ VCAM-1

Cross the BBB

↓


↓


↓

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




Cross the BBB

↓


↓


↓

Myelin damage

NatalizumabVLA-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


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

THANK YOU

neuroimmunology

Health & Medicine

dendritic cells

thelper cells

langerhans cells

regulator t cells

cd45cd4 t cells

polymorphonuclear cells

kupffer cells

endothelial cells