Autoimmunity disorders occur when the immune system mounts an attack against the body's own tissues and organs. They are difficult to diagnose due to nonspecific initial symptoms, fluctuating symptoms, and the potential for multiple autoimmune conditions. Diagnostic methods include initial laboratory tests of inflammatory markers and autoantibodies, immunological studies, flow cytometry to analyze immune cells, cytokine studies, and examination of major histocompatibility complex genes associated with autoimmunity. A variety of autoantibodies against nuclear, cytoplasmic, and other cellular components can indicate autoimmune disease patterns and targets.
3. DEFINITION
• Three requirements to call it Autoimmunity :
1. The presence of an immune reaction
specific for some self antigen or self tissue.
2. Evidence that such a reaction is not
secondary to tissue damage but is of
primary pathogenic significance.
3. The absence of another well-defined cause
of the disease.
4. HISTORY
Julius Donath and Karl Landsteiner (1904)reported
autoantibodies can cause disease by showing that
autoantibodies (‘hemolysins’) caused paroxysmal
cold hemoglobinuria.
5. Introduction
• Autoimmune diseases is a group of disorders
in which tissue injury is caused by humoral (by
auto-antibodies) or cell mediated immune
response (by auto-reactive T cells) to self
antigens.
• An autoimmune disorder may result in:
The destruction of one or more types of body tissue
Abnormal growth of an organ
Changes in organ function
13. Immune tolerance
• Definition: Immunological tolerance occurs when an
immunocompetent host fails to respond to an
immunogenic challenge with a specific antigen.
• * a state of unresponsiveness specific for a given
antigen
• * It is specific (negative) immune response
• * It is induced by prior exposure to that antigen
• * While the most important form of tolerance is non-
reactivity to self antigens, it is possible to induce
tolerance to non-self antigens. When an antigen
induces tolerance, it is termed tolerogen.
14. • Immune tolerance
• * Tolerance is different from non-specific
immunosuppression and immunodeficiency. It
is an active antigen-dependent process in
response to the antigen.
• * Like immune response, tolerance is specific
and like immunological memory, it can exist in
T cells, B cells or both and like immunological
memory, tolerance at the T cell level is longer
lasting than tolerance at the B cell level.
15. TOLERANCE – GENERAL PROPERTIES
• Immature or developing lymphocyte is more
susceptible to tolerance induction than
mature one
• 1.Tolerance to antigens is induced even in
mature lymphocytes under special conditions
• 2.Tolerance of T lymphocytes is a particularly
effective for maintaining long-lived
unresponsiveness to self antigens
16.
17. Central tolerance: fates of immature
self-reactive lymphocytes
• Induced by antigen in generative lymphoid organs
(thymus for T cells, bone marrow for B cells), and high-
affinity (“strong”) recognition of the antigens
• Immature lymphocytes undergo apoptosis upon
encounter with antigens (negative selection) Eliminates
high-affinity self-reactive (potentially most dangerous)
lymphocytes
• Some self-reactive T cells that encounter self antigens
in the thymus develop into regulatory T cells and
immature B cells in the bone marrow change their
receptors (rendered harmless)
18.
19. Mechanisms of tolerance induction
• * Clonal deletion – physical elimination of cells
from the repertoire during their lifespan
• * Clonal anergy – downregulating the intrinsic
mechanism of the immune response such as
lack of costimulatory molecules or insufficient
second signal for cell activation
• * Suppression – inhibition of cellular activation
by interaction with other cells:
• (Treg – CD4+CD25+ T lymphocytes)
20. Mechanism of tolerance induction
• Clonal deletion:
• Functionally immature cells of a clone
encountering antigen undergo a programmed
cell death, as auto-reactive T-cells are
eliminated in the thymus following interaction
with self antigen during their differentiation
(negative selection).
21. Mechanism of tolerance induction
• Clonal anergy:
• * Auto-reactive T cells, when exposed to
antigenic peptides which do not possess co-
stimulatory molecules (B7-1 or B7-2), become
anergic to the antigen.
• * Recognition of such antigens may lead to
signaling block and/or engagement of
inhibitory receptors
22.
23.
24. Mechanism of peripheral tolerance
• Ignorance: Never encounter Self Ag
• Anergy: unresponsiveness
• Self reactive T cell interact with APC but co-stimulatory signal blocked
• Immunomodulatory molecules like CTLA4 binding instead of CD 28 on T cell
• Phenotypic skewing: after activation via APC (with Self Ag)---Non
pathogenic cytokines release
• Activated self reactive Tcell---Upregulation of Fas Ligand---apoptosis
• Regulatory T cells (TREG Cells)-can down regulate self reactive T cell (by
IL-10, TGF-b)
• Sequestration of self Ag: lens protein
25. • Antigen can be Tolerogen or Immunogens
• Co-stimulatory molecules play an important
role
• Tolerance is antigen specific
26. Immune tolerance: factors that influence
immunity vs. tolerance
• * The stage of differentiation of lymphocytes
at the time of antigen confrontation
– * The site of encounter
• * The nature of cells presenting antigenic
epitopes
• * The number of lymphocytes able to respond
• * Microenvironment of encounter (expression
of cell adhesion molecules, influence of
cytokines etc.)
27. Immunologically Privileged Sites
• * Sites in the body where foreign antigens or
tissue grafts do not elicit immune responses
• * These antigens do interact with T cells, but
instead of destructive IR they induce tolerance or
a response innocent to the tissue
• Immunosuppressive cytokines such as TGF-beta
seem to be resposible for such unusual response
• * The sites include: brain, eye, testis, uterus
(fetus)
28. Failure of tolerance Autoimmunity
• Failure of Tolerance to protect host from self-
reacting lymphocytes
• Destruction of self proteins, cells, and organs
by auto-antibodies or self-reactive T cells
• 3% to 8% of individuals in the industrialized
world
29. Factors responsible for promoting
tolerance
• High dose of antigen
• Persistence of antigen
• Route of administration
• Adjuvents
• Low level of co-stimulators
• Presentation of antigen by
immature/unactivated antigen-presenting
cells (APCs)
30.
31. • All together
– Autoimmunity may be due to immunological,
Genetic, Viral, Drug induced, & hormonal
mechanisms
– Number of immunological mechanism all
leading to abnormal B or T-cell production.
– Most instances Diseases by multiple mechanism
difficulty in Rx
32.
33. Mechanisms
• Antigenic alteration
• Sequestered Ag
• Cross reacting foreign Ag
• Molecular mimicry
• Polyclonal activation of B cell
• Altered T or B cell function
35. Sequestered Ag
• Sequestered Ag: Self Ab present in closed
system not accessible to immune system
• Lens protein
• Immunological tolerance not established
during foetal life
• Penetrating injury---leak of lens protein—
immune response—injury to other eye
36. Sequestered Ag
• Sperm Ag—Puberty
• Mumps---damage to BM seminiferous
tubules—immune response---Orchitis
37. Cross reacting foreign Ag
• Similary b/w some foreign & Self Ag
• Indivisual Nerve tissue damage-antirabies
immunization of human with neural vaccine of
infected sheep brain
• Streptococcal M protein—heart ms—Heart
damage
• Nephritogenic strain streptococcus-- GN
38. Molecular mimicry
• Identical peptide sequence in epitopes b/w
microorganism & Self Ag
• HLA B27- Arthritogenic strain of S. flexneri
• Joint membrane- M. tuberculoisis
• Myocardium- Coxsackie B virus
39.
40. Polyclonal activation of B cell
• Ag--- corresponding B cell activation
• Polyclonal activation of B cells:
– Chemical (2 ME)
– Bacterial product (PPD, LPS)
– Enz (Trypsin)
– Antibotics (Nystatin)
– Infection (Mycoplasma, EBV, Malaria)
41. Altered T or B cell function
• Enhanced Helper T cell
• ↓↓ Suppressor T cell function
• Defect in thymus
• Stem cell development
• Macrophage function
• Idiotype-antiidiotype network defect
52. Disease
Hashimoto’s Ds Enlargement of thyroid
Hypothyrodism or
Frank myxedma
Glandular structure-replacement
with lymphoid tissue
Ab- to thyoglobulin, acinar
colloid, Microsomal Ag,
thyroid cell surface
components
Thyrotoxicosis
(Grave’s Ds)
↑↑↑ hormone IgG Ab (to thyroid
membrane Ag) act as Long
acting thyroid stimulator
(LATS)
Addison ds Lymphocytic infiltration of
adrenal &
circulating Ab to Zona
glomerulosa
Autoimmune
orchitis
Mumps Lymphocytic infiltration of
Testes &
circulating Ab to sperm &
germinal cell
53. Disease
Myasthenia gravis Thyorid lymphoid hyperplasia
Numerous germinal center
Ab Ach Receptor on
myoneural junction of
striated Ms---impairment
of Ms Contraction
Autoimmune
Disease of eye
Phacoanaphylaxis- Cataract Sx –
intraocular inflammation
Symathetic ophthamia-
Performating injury to one
eye
Pernicious Anaemia Ab to parietal cell of gastric
mucosa- Achlorhydria, Atrophic
gastritis
Ab to Intrinsic Factor---Vit B12 def
Autoimmune
Disease of Nervous
system
Neuroparalytic accidents
following- neural vaccine—Rabies
GBS- idiopathic polyneuritis
Autoimmune ds of
Skin
Pemphigus vulgaris- Ab to
intracellular adhesion protein
desmoglein
Bullous pemphigoid- Ab
dermoepidermal junction
Ab in Dermatitis
herpetiformis
54.
55.
56. – Variety of AutoAb
• Nuclei
• Intracytoplasmic cell constituents
– LE cell- Neutrophils containing LE Bodies (large
pale homogenous body) almost filling cytoplasm
– Antinuclear Ab (ANA)—Sensitive but not specific
• Pattern: homogenous, Peripheral, speckled, nucleolar
– Anti DNA Ab- ds
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64.
65. • The diagnostic methods of autoimmune
diseases includes,
• Initial laboratory evolution
• Immunological studies
• Inflammatory markers
• Flowcytometry
• Cytokine studies
• Major histocompatibility complex
66.
67.
68.
69. • Q: Why are autoimmune diseases challenging to
diagnose?
• A: Diagnosis is challenging for several reasons:
• 1. Patients initially present with nonspecific symptoms such
as fatigue, joint and muscle pain, fever, and/or weight
change.
• 2. Symptoms often flare and remit.
• 3. Patients frequently have more than 1 autoimmune
disease.
• According to a survey by the Autoimmune Diseases
Association, it takes up to 4.6 years and nearly 5 doctors for
a patient to receive a proper autoimmune disease diagnosis