Autoimmunity 2022

Autoimmunity
IFEORAH I.M (Ph.D)
NOV 2022
Learning outcome
• Understand the concepts of autoimmunity and disease
• Know the features of major autoimmune diseases

Autoimmunity/Auto immune Disease (AID)
• The immune system’s three basic functions are Defence, Surveillance and Homeostasis
• Autoimmunity is inappropriate response against self Antigens due to breakdown of

immunological Tolerance.
• Autoimmune diseases occur when autoimmune responses result in inflammation and

tissue damage.
• Ideally immune system should:

• responds only to foreign Ag
• activate immune effector mechanisms that selectively clear the foreign Ag
without damage to the host
• effector mechanisms turned off when no longer needed.
Etiology of autoimmune disorders
Source : Epigenetic Basis of Autoimmune Disorders in Humans

Genetic basis of autoimmunity Infections and autoimmunity
• Infections trigger autoimmune reactions

• Multiple genes are associated with
autoimmunity • Some autoimmune diseases are prevented by infections (type
– Most human autoimmune diseases are
1 diabetes, multiple sclerosis, others? -- increasing incidence
multigenic
in developed countries): mechanism unknown
– Single gene defects reveal pathways of
self-tolerance and why it fails (e.g.
The “hygiene hypothesis”
AIRE, Fas, Foxp3, many others) but
are not involved in most, common
autoimmune diseases Other environmental factors
Hormones
• Genes include HLA, many others Gender bias of autoimmune diseases
– Each gene individually makes a small Mechanisms still not defined
contribution
UV exposure
SLE (increased burden of nuclear antigens from dying cells?)
Smoking and periodontal infections predispose to RA

Production of citrullinated peptides?
6
Organ specific AID
SYSTEMIC AUTOIMMUNE DISEASE
Mechanisms
• molecular mimicry,
• Defective regulation of the anti-self response
• Polyclonal B –cell activation (unAg specific activation as seen in eg Infectious

mononucleosis and EBV
• modification of self antigens through microbes and drugs,
• changes in the availability of self antigen
• Inappropriate expression of class II MHC Molecules

Molecular mimicry
• Immune response may be generated against an epitope that is identical, or nearly identical, in
both a microbe and host tissue, resulting in attack on host tissue by the same effector
mechanisms which are activated to eliminate the pathogen.
molecular mimicry
Activation of anergic anti-self B cells. The BCR on an anti-self B cell binds to self/microbial Ag complex. The B cell
presents the microbial component of the complex to a T cell and receives T cell help for activation (second signal). This is
also called the ‘T cell bypass’ mechanism of autoimmunity since T cell help for self is bypassed by presentation via a non-
self antigen.
Polyclonal B –cell activation
• Some microbes or their products activate lymphocytes independently of their antigenic
specificity, i.e are polyclonal activators.
• Gram-negative bacteria, CMV, EBV are polyclonal activators.
• They induce the proliferation of numerous clones of B cells that express IgM in the absence of
T cells. If B cells reactive to self-antigens are activated by this mechanism, auto-antibodies can
appear.
• In infectious mononucleosis, caused by EBV, a variety of auto-antibodies are produced,

including autoantibodies reactive to T and B cells, rheumatoid factors, and antinuclear
antibodies.
Release of Sequestered Ag
• Tolerance induction occurs mainly during embryonic development,
• Ag which are absent or anatomically separated (sequestered) from the immune

system during this period are not recognized as self.
• These Ag are either present in too low amounts to stimulate autoimmunity or are
sequestered in immunologically privileged sites.
• In later life, these antigens may be released as a result of trauma or infection. They
may then stimulate lymphocytes that have escaped tolerance and induce the
development of autoimmune disease.
Inappropriate expression of MHC Class II molecules
• The pancreatic beta cells of individuals with IDDM express high levels of both class
I and class II MHC molecules, whereas healthy beta cells express lower levels of
class I and do not express class II at all.
• certain agents can induce some cells that should not express class II MHC molecules
to express them. Eg the T-cell mitogen phytohemagglutinin(PHA)has been shown to
induce thyroid cells to express class II molecules.
• IFN-gamma also induces increases in class II MHC molecules on a wide variety of

cells. If IFN gamma induces class II MHC expression on non-antigen-presenting
cells, inappropriate T-cell activation might follow, with autoimmune consequence.
Effector Mechanism in AID
• Effective mechanism can follow any of the 3 classical HSRXN II, III,IV
• Direct cell destruction: (Type II)

• Autoantibodies can bind to self cells and either alone or with complement cause
damage.
• This can be mediated through opsonization via Fc receptors (Warm auto Ab or

C3 receptors on phagocytic cells (Cold Auto-Ab).
• An example of this is IgG autoantibodies binding to red blood cells in

autoimmune hemolytic anemia.
• Modulation of cell function: (Agonist /antagonist)
Antibodies to certain self cell surface molecules can either interfere with or enhance the functional activity of the cell.
Eg, Abs to the acetylcholine receptor in myasthenia gravis block their effective interaction with acetylcholine
In Graves’ disease, Abs to the TSH receptor over stimulate the thyroid
• Autoantibodies can form damaging immune complexes:
• Circulating IC, whether composed of autologous or foreign Ag, can result in

damage to tissue by complement activation and triggering release of mediators
from Fc receptor-bearing cells.
• Immune complexes can deposit in the glomeruli, especially in SLE, leading to

kidney damage or, in blood vessels, to vasculitis.
• Cell mediated immunity in pathogenesis:
• Although autoantibodies have been most firmly linked to autoimmune disease , it

is clear that cell mediated immunity plays an essential part in pathogenesis in
some, if not all autoimmune disorders.
• T cells not only play a helper role in the development of autoimmune disease but
also a direct role in tissue inflammation. Eg Rheumatoid Arthritis, multiple
sclerosis, insulin dependent diabetes mellitus
• Thanks

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Autoimmunity

IFEORAH I.M (Ph.D)

• Understand the concepts of autoimmunity and disease

• Know the features of major autoimmune diseases

• Autoimmunity is inappropriate response against self Antigens due to breakdown of

• Autoimmune diseases occur when autoimmune responses result in inflammation and

• Ideally immune system should:

Source : Epigenetic Basis of Autoimmune Disorders in Humans

• Infections trigger autoimmune reactions

Smoking and periodontal infections predispose to RA

• Defective regulation of the anti-self response

• Polyclonal B –cell activation (unAg specific activation as seen in eg Infectious

• modiﬁcation of self antigens through microbes and drugs,

• changes in the availability of self antigen

• Inappropriate expression of class II MHC Molecules

• Gram-negative bacteria, CMV, EBV are polyclonal activators.

• In infectious mononucleosis, caused by EBV, a variety of auto-antibodies are produced,

• Ag which are absent or anatomically separated (sequestered) from the immune

• IFN-gamma also induces increases in class II MHC molecules on a wide variety of

• Direct cell destruction: (Type II)

• This can be mediated through opsonization via Fc receptors (Warm auto Ab or

• An example of this is IgG autoantibodies binding to red blood cells in

• Autoantibodies can form damaging immune complexes:

• Circulating IC, whether composed of autologous or foreign Ag, can result in

• Immune complexes can deposit in the glomeruli, especially in SLE, leading to

• Although autoantibodies have been most ﬁrmly linked to autoimmune disease , it

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