Neuro immunology basics

Immune System
• Normal Functions
Immunity against micro-organisms and pathogens
Wound healing
Tumor surveillance
• Disorders Resulting from Immune System Dysfunction
Autoimmunity
Immune-mediated disorders
Graft rejection

Adaptive and Innate Immunity
The immune system has two functional divisions:
• The innate immune system
• The adaptive immune system.

Adaptive and Innate Immunity
• The innate immune system consists :
Skin: The exterior surface of the body, primarily the skin, is the body's primary defense against
foreign pathogens.
Phagocytes are cells capable of phagocytosing foreign pathogens. They include
polymorphonuclear cells, monocytes, and macrophages.
Natural killer (NK) cells—NK cells recognize cell surface molecules on virally infected or
tumor cells.
Complement system ??

Complement system
• They are protein synthesized in the liver.
• They are inactivated proteolysis enzymes.
• Numbered from [1- 9 ] according cascade of activation.
• When activated complement occurs it breaks down into portion eg: C5a and
C5b.
• The b segment is the large one and in turn will activate the next step in the
cascade.

Immunoglobulins
1. Antibodies (Igs), antibodies are able to specifically recognize a
variety of free antigens.
2. Igs are produced by B cells and are present on their cell surface.
3. Antibodies recognize specific microbial and other antigens through
their antigen-binding sites and bind to cells via their Fc receptors.

Immunoglobulins
4. Each molecule consists of two identical polypeptide light chains
(kappa [κ] or lambda [λ]) linked to two identical heavy chains.
6. According to the biochemical nature of the heavy chain, Igs are
divided into five main classes: IgM, IgD, IgG, IgA, and IgE. These may
be further divided into subclasses depending on differences in the heavy
chain.

B cells
 B cells: The primary function of B cells is to produce antibody.
 Antigen binding to B cells stimulates proliferation and maturation of that
particular B cell, with subsequent enhancement of antigen-specific antibody
production, resulting in the development of antibody-secreting plasma cells.
 Most B cells express class II major histocompatibility complex (MHC)??
antigens and have the ability to function as APCs??

Major histocompatibility complex
 Major histocompatibility complex gene products or the human leukocyte antigens
(HLAs) serve to distinguish self from nonself.
 They serve the important function of presenting antigen to the appropriate cells.
 They are classified into MHC I and II.
 Class I antigens are expressed on all nucleated cells, whereas class II antigens are
constitutively expressed only on dendritic cells, macrophages, and B cells
,endothelial cells, and astrocytes.

 In humans, class I molecules are HLA-A, B, and C, whereas the class II
molecules are HLA-DP, DQ, and DR.
 Each one of these subclasses has wide range of alleles.
 Class I antigens regulate the specificity of cytotoxic CD8 + T cells, which
are responsible for killing cells bearing viral antigens .
 The function of class II MHC gene products appears to be to regulate the
specificity of T-helper cells.

Toll like receptors [ TLR]
TLR are pathogen recognition
receptors .
They recognize pathogen associated
molecular pattern.
They present on cell surface and
intracellular.

T Lymphocytes
 Differentiation of T cells occurs in the thymus, and every T cell that
leaves the thymus is conferred with a unique specificity for recognizing
antigens.
 T cells may be divided into two groups on the basis of expression of
either the CD4 + or CD8 + marker????.
 The first step in activation is binding to APC by T cell receptor ( TCR).

T Lymphocytes
The TCR consists of two glycosylated polypeptide chains, alpha (α) and
beta (β), of 45,000 and 40,000 dalton molecular weight, respectively.
T cells can only recognize short peptides that are associated with MHC
molecules.

T Lymphocytes
Upon stimulation of their TcR in the presence of
co-stimulatory signals?? naïve T cells in the
peripheral immune compartment develop into
different subsets of effector T helper cells.
This differentiation process is directed by a
specific cytokine milieu as indicated leading to
the expression of transcription factors specific for
the respective lineages.

Cluster of differentiation [ CD]
 They are group of proteins
presents on cell surface which are
expressed during different stages
of maturation and differentiation.
 CD were numbered 1-340
according to discovery order.

Cluster of differentiation [ CD]
CD3 – 4- 8 on T cells

Organization of the Immune
Response

Organization of the Immune Response
•Initiation of the Immune Response.
•Regulation of the Immune Response
•Termination of an Immune Response

Initiation of the Immune Response.
1- Antigen Presentation.
2- Accessory Molecules for T-Cell Activation
3- Co-stimulatory Molecules??
4- cell migration ??
5- Accessory Molecules for B-Cell Activation??

Co-stimulatory Molecules
Costimulatory molecules serve as a “second signal” to facilitate T-cell activation.
Members of the integrin families including vascular cell adhesion molecule 1
(VCAM-1), intercellular adhesion molecule (ICAM-1), and leukocyte function
antigen 3 (LFA-3) can provide costimulatory signals, but they also play critical roles
in T-cell adhesion, facilitate interaction with the APCs, mediate adhesion to
nonhematopoietic cells such as endothelial cells, and guide cell traffic

Cell migration
Molecules primarily involved in cell migration into tissues include
chemokines, integrins, selectins, and matrix metalloproteinases (MMPs).
Chemokines constitute a large family of chemoattractant peptides that
regulate the vast spectrum of leukocyte migration events through interactions
with chemokine receptors.
The integrin family includes VCAM-1, ICAM-1, LFA-3, CD45, and CD2 and
mediates adhesion to endothelial cells and guiding cell traffic.

Cell migration
Selectins facilitate the rolling of leukocytes along the surface of endothelial cells .
The MMPs are a family of proteinases secreted by inflammatory cells; MMPs
digest specific components of the extracellular matrix, thereby facilitating
lymphocyte entry through basement membranes including the blood–brain barrier
(BBB).

Accessory Molecules for B-Cell Activation
Like T cells, B cells require accessory molecules that supplement signals
mediated through cell-surface Igs.
B cells can respond to proteins, peptides, polysaccharides, nucleic acids,
lipids, and small chemicals.
B cells responding to peptide antigens are dependent on T-cell help for
proliferation and differentiation, and these antigens are termed thymus-
dependent (T-dependent).

Regulation of the Immune Response

Regulation of the Immune Response
•Cytokines
•Chemokines

Cytokines
Cytokines are broadly divided into the following categories:
(1) growth factors such as IL-1, IL-2, IL-3, and IL-4 and colony-stimulating factors.
(2) activation factors, such as interferons (α, β, and γ, which are also antiviral).
(3) regulatory or cytotoxic factors, including IL-10, IL-12, transforming growth
factor beta (TGF-β), lymphotoxins, and tumor necrosis factor alpha (TNF-α)
(4) chemokines that are chemotactic inflammatory factors, such as IL-8,
Macrophage Inflammatory Proteins(MIP-1α, and MIP-1β).

Cytokine Cell source Cells principally affected Major functions
IL-1 Most cells; macrophages, microglia Most cells; T cells, microglia,
astrocytes, macrophages
Costimulates T- and B-cell activation
Induces IL-6, promotes IL-2 and IL-2R
transcription
Endogenous pyrogen, induces sleep
IL-2 T cells T cells, NK cells, B cells Growth stimulation
IL-3 T cells Bone marrow precursors for all
cell lineages
Growth stimulation
IL-4 T cells B cells, T cells, macrophages MHC II upregulation
Isotype switching (IgG1, IgE)
IL-6 Macrophages, endothelial cells,
fibroblasts, T cells
Hepatocytes, B cells, T cells Inflammation, costimulates T-cell
activation
MHC I upregulation, increases vascular
permeability
Acute phase response (Schwartzman
reaction)
IL-10 Macrophages, T cells Macrophages, T cells Inhibition of IFN-γ, TNF-α, IL-6
production

Cytokine Cell source Cells principally affected Major functions
IL-12 Macrophages, dendritic cells T cells, NK cells Costimulates B-cell growth, CD4
+
T H 1
cell differentiation, IFN-γ synthesis,
cytolytic function
IL-17 T cells Neutrophils, T cells, epithelial
cells, fibroblasts
Host defense against gram-negative
bacteria, induction of neutrophilic
responses
Induction of proinflammatory cytokines
IFN-γ T cells, NK cells Astrocytes, macrophages,
endothelial cells, NK cells
MHC I and II expression
Induces TNF-α production, isotype
switching (IgG 2 )
Synergizes with TNF-α for many functions
TNF-α Macrophages, microglia (T cells) Most cells, including
oligodendrocytes
Cytotoxic (e.g., for oligodendrocytes),
lethal at high doses
Upregulates MHC, promotes leukocyte
extravasation
Induces IL-1, IL-6, cachexia; endogenous
pyrogen
Lymphotoxin
(TNF-β)
T cells Most cells (shares receptor with
TNF-α)
Cytotoxic (at short range or through
contact)
Promotes extravasation
TGF-β Most cells; macrophages, T cells,
neurons
Most cells Pleiotropic, antiproliferative, anticytokine
Promotes vascularization, healing

Cytokines
There are cytokines that can down regulate immune responses.
IFN-α and IFN-β, can modulate antibody response by their
antiproliferative properties.
TGF-β can also decrease cell proliferation.
IL-10, a growth factor for B cells, inhibits the production of IFN-γ and
thus may have anti-inflammatory effects.

Cytokines
Th 1 cells secrete IFN-γ, IL-2, and TNF-α. These cytokines exert
proinflammatory functions and, in T H 1-mediated diseases such as MS,
promote tissue injury.
In contrast, the Th 2 cytokines IL-4, IL-5, IL-6, IL-10, and IL-13
promote antibody production by B cells, enhance eosinophil functions,
and generally suppress cell-mediated immunity (CMI).

Chemokines
Chemokines are a group of molecules that aid in leukocyte mobility and directed
movement.
Chemokines may be grouped into two subfamilies based on the configuration and
binding of the two terminal cysteine residues,( C-C family and C-X-C family).
Chemokines are produced by a variety of immune and nonimmune cells.

Termination of an Immune Response

The primary goal of the immune response is to protect the organism
from infectious agents and generate memory T- and B-cell responses
that provide accelerated and high-avidity secondary responses on re-
encountering antigens.
It is desirable to terminate these responses once an antigen has been
cleared.

• B-Cell Inhibition
• Immunoglobulin
• T Cells

B-Cell Inhibition
In most instances the formation of antigen–antibody
complexes can themselves result in the inhibition of B-
cell differentiation and proliferation through binding of
the Fc receptor to the CD32 (FcγRIIB) receptor on the
surface of the B cell.

Immunoglobulin
The variable regions of the Ig and the TCR molecule
represent novel proteins that can act as antigens. Antigenic
variable regions are called idiotopes , and responses against
such antigens are called anti-idiotypic.
this hypothesis still under research

T Cells Inhibition
Repeated stimulation of T cells may lead to activation-
induced cell death through apoptosis.
Regulatory cells generally inhibit the immune response
through secretion of cytokines.

Self-Tolerance
An organism's ability to maintain a state of
unresponsiveness to its own antigens is termed self-
tolerance .
Self-tolerance may be broadly categorized as either
central or peripheral tolerance.

Central Tolerance
Bone marrow stem cells migrate to the thymus, thereby
becoming T cells.
In the thymus medulla, thymocytes that display a high
affinity toward self-antigen are deleted by apoptosis, a
process called negative selection.

Peripheral Tolerance
Self-reactive lymphocytes may escape central tolerance;
therefore, peripheral mechanisms exist to maintain self-
tolerance.
Peripheral tolerance is maintained through clonal
anergy or clonal deletion.

Anergy Due to Failure of T-Cell Activation

Regulatory T Cells
Regulatory T cells (T reg ) function to down regulate CD4 and CD8 T-
cell responses.
Regulatory T cells suppress T-cell proliferation through a variety of
mechanisms, including the production of immunosuppressive cytokines
or through the expression of inhibitory molecules such cytotoxic T-
lymphocyte-associated protein 4 (CTLA-4).

Immune System and Central Nervous
System

Immune Privilege in the Central Nervous System
Important factors relevant to immunological responses in the CNS are:
(1) absence of lymphatic drainage.
(2) the blood–brain barrier.
(3) the low level of expression of MHC factors.
(4) low levels of potent APCs, such as dendritic or Langerhans cells.
(5) the presence of immunosuppressive factors such as TGF-β .

Neuro immunology basics

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