Autoimmunity

1. AUTOIMMUNITY
Presented by Moderator :
Dr.Varughese George Dr. K Shanmughasamy

2. CONTENTS
 DEFINITION
 HISTORY
 TOLERANCE
 FACTORS INFLUENCING AUTOIMMUNITY
 AUTOIMMUNE DISEASES – CLASSIFICATION
 SYSTEMIC LUPUS ERYTHEMATOSUS
 HASHIMOTO’S THYROIDITIS
 GRAVE’S DISEASE
 RHEUMATOID ARTHRITIS
 SJOGERN SYNDROME
 PERNICIOUS ANEMIA
 AUTOIMMUNE HEMOLYTIC ANEMIA
 TYPE 1 DIABETES MELLITUS
 MYASTHENIA GRAVIS
 MULTIPLE SCLEROSIS
 SUMMARY

3. DEFINITION
Autoimmunity is
 breakdown of the immune system’s ability to discriminate between self
and nonself.
 condition in which structural or functional damage is produced by
action of immunologically competent cells or antibodies against the
normal components of the body.
 5-7 % of adults affected, 2/3rds involving women.
 > 40 human diseases, autoimmune in origin.

4. DEFINITION
3 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.

5. HISTORY
 Serge Metalnikoff (1900) reported that some animals
were able to form antibodies against their own
spermatozoa.
 Paul Ehrlich (1901) rejected the concept that an
organism's immune system could attack the
organism's own tissue calling it "horror autotoxicus".
 Julius Donath and Karl Landsteiner (1904)reported
autoantibodies can cause disease by showing that
autoantibodies (‘hemolysins’) caused paroxysmal cold
hemoglobinuria.

6. HISTORY
 Ernst Witebsky and Noel Rose (1956) were able to
induce an experimental autoimmune thyroiditis
mediated by autoantibodies.
 Witebsky (1957)postulated in Witebsky postulates,
modified later (1994) for placing a disorder under
Autoimmune disease.
 There are three considerations :
 Direct evidence from transfer of pathogenic
antibody or pathogenic T cells.
 Indirect evidence based on development of the
autoimmune disease in experimental animals.
 Conditional evidence from clinical clues, from
signs and symptoms of patient.

7. TOLERANCE
 Normal immune system must differentiate between self and non-self.
 Immunologic tolerance  unresponsiveness to an antigen that is induced
by exposure of specific lymphocytes to that antigen.
 Failure of self tolerance 
 lack of responsiveness to an individual’s own antigens.
 underlies our ability to live in harmony with our cells and tissues.
Autoimmunity results from the loss of self-tolerance.
 Types :
 Central Tolerance.
 Peripheral Tolerance.

8. TOLERANCE
• Central tolerance: Immature self-reactive lymphocytes that recognize self
antigens in generative (“central”) lymphoid organs die by apoptosis; other
fates .
• Peripheral tolerance: Mature self-reactive lymphocytes that recognize
self antigens in peripheral tissues are inactivated (anergy), killed
(deletion) or suppressed.

9. CENTRAL TOLERANCE
Immature T cells that recognize self antigens in the central (generative) lymphoid
organs, some
• are killed by apoptosis - Negative selection or deletion in Thymus.
• escape killing and differentiate into regulatory T cells.
In the B-cell lineage, some
• are killed by apoptosis.
• some of the self-reactive lymphocytes switch to new antigen receptors that are not
self-reactive - Receptor editing in Bone Marrow.

10. Deletion of self-reactive T cells in the thymus:
how are self antigens expressed in the thymus?
•Many self antigens are processed and presented
by thymic APCs in association with self MHC.
•Any immature T cell that encounters a self
antigen undergoes deletion/negative selection
and the T cells that complete their maturation are
thereby depleted of self-reactive cells
•AIRE (autoimmune regulator) is a regulator
of gene transcription that stimulates thymic
expression of many self antigens which are
largely restricted to peripheral tissues .
•Mutations in AIRE gene gives rise to Autoimmune
Polyendocrine Syndrome in which T cells specific
for multiple self antigens escape deletion and
attack tissues expressing the self antigens.

11. PERIPHERAL TOLERANCE
Self-reactive T cells that escape negative selection in the thymus can potentially
wreak havoc unless they are deleted or effectively muzzled.
Several mechanisms in the peripheral tissues that silence such potentially
autoreactive T cells :
Anergy- functionally inactive .
or
Suppression by regulatory T-lymphocytes.
or
Deletion by activation induced cell death by
 Activation of pro-apoptotic member of Bcl family called BIM.
 Fas-Fas ligand system.

12. PERIPHERAL TOLERANCE
Anergy - functional inactivation of lymphocytes induced by encounter with
antigens.
Activation of T cells requires two signals:
 Signal 1 : recognition of peptide antigen in association with self MHC
molecules on APCs.
 Signal 2 : costimulatory signals (e.g., through B7 molecules) provided by the
APCs.
If Signal 2 is not delivered due to weak expression of costimulatory molecules
The T cell becomes anergic and cannot respond to the antigen.

13. PERIPHERAL TOLERANCE
Suppression by regulatory T cells - The responses of T cells to self
antigens may be actively suppressed by regulatory T cells.
 Regulatory T cells are CD4+ cells that express high levels of
CD25 (IL-2 receptor a chain)
 Generated by self antigen recognition in the thymus or
peripheral tissues
 Generation requires a transcription factor called Foxp3
 Mutations in FoxP3 gene are the cause of a severe
autoimmune disease IPEX in humans.
associated with deficiency of regulatory T cells.

14. PERIPHERAL TOLERANCE
Activation-induced cell death - apoptosis of mature lymphocytes as a
result of self-antigen recognition.
Stimulation of T cells by self antigen triggers apoptosis by
 Engagement of death receptor Fas engaged by its ligand coexpressed on the
same or neighboring cells - Death receptor pathway.
Mutations in the Fas gene are responsible for an autoimmune disease - ALPS.
or
• Imbalanced expression of pro-apoptotic proteins - member of Bcl family
called BIM (Bcl-2-like protein 11) Mitochondrial pathway

15. The factors that lead to a failure
of self-tolerance and the
development of autoimmunity
include :
1. inheritance of
susceptibility - genes that
may disrupt different
tolerance pathways.
2. infections and tissue
alterations that may
expose self-antigens and
activate APCs and
lymphocytes in the tissues.

16. FACTORS INFLUENCING AUTOIMMUNITY

17. Genetic Factors
 There is increased expression of Class II HLA antigens on tissues
involved in autoimmunity.
 There is increased familial incidence of some forms of the
autoimmune disorders.
 There is higher incidence of autoimmune diseases in twins
(monozygotic > dizygotic) favouring genetic basis.
 Most human autoimmune diseases are associated with multiple genes.
 Genome wide association studies are revealing genetic polymorphisms associated
with autoimmune diseases.

18. Immunological factors
 Polyclonal activation of B cells by stimuli such as infection with
microorganisms & their products bypasses T cell tolerance.
 Generation of self-reacting B cell clones bypasses T cell tolerance.
 Decreased T suppressor and increased T helper cell activity lead to high
levels of autoantibody production by B cells contributing to autoimmunity.
 Fluctuation of anti-idiotype network control may cause failure of
mechanisms of immune tolerance.
 Sequestered ‘Self-antigens’ may act as ‘foreign-antigens’ if introduced into
the circulation later.

19. Sequestered antigens
Certain self anigens are present in closed systems and
are not accessible to immune apparatus.
These are known as sequestered antigens
( HIDDEN ANTIGENS )

20. Ag related from hidden location
Many self Ag are found in hidden location eg. CNS ,Testes ,Eye
(CORNEA)
Organ damage
Hidden Ag released
Reaches blood stream
Encounter Ag sensitive cells
Stimulate autoimmunity

21. Examples of Sequestered Antigens
Myelin basic protein (MBP), associated with MS.
Sperm-associated antigens in some individuals following
vasectomy.
Lens and corneal proteins of the eye following infection or
trauma.
Heart muscle antigens following myocardial infarction.

22. Enviromental factors
 Ultraviolet (UV) radiation causes cell death and maylead to the
exposure of nuclear antigens, which elicit pathologic immune
responses in lupus.
 Smoking is a risk factor for rheumatoid arthritis, perhaps because it
leads to chemical modification of self antigens.
 Strong gender bias, with many of these diseases being more common
in women > men owing to hormones and other mechanisms.

23. Role of Infections and Tissue Injury
 Molecular mimicry : Viruses and other microbes may share cross-
reacting epitopes with self antigens, such that responses may be
induced by the microbe but may attack self tissues. e.g. Rheumatic
heart disease.
 Microbial infections with resultant tissue necrosis and inflammation
can cause upregulation of costimulatory molecules on APCs in the
tissue favoring breakdown of T cell anergy and subsequent T cell
activation.

24. Autoimmune Diseases

25. Criteria for diagnosis of autoimmune diseases.
LABORATORY EVIDENCE
1. Presence and documentation of relevant autoantibodies in the
serum
2. Demonstration of T cell reactivity to self antigen
3. Lymphocytic infiltrate in the pathologic lesion
4. Production of cytokines by helper T cells e.g. interferon,IL4
5. Evidence to support production of pathologic lesions in the
tissue by transplacental transmission
6. Transfer of an autoimmune disease to an experimental animal by
administration of autoantibodies.

26. Criteria for diagnosis of autoimmune diseases.
CLINICAL EVIDENCE
1. Association of other autoimmune disease.
2. Improved therapeutic response to immunosuppressive
agents.
3. Family history of autoimmune disease.

27. Systemic lupus erythematosus
(SLE)
 Systemic lupus erythematosus (SLE) is a multisystem autoimmune
disease of protean manifestations and variable clinical behavior.
 Clinically, it is an unpredictable, remitting and relapsing disease of
acute or insidious onset that may involve virtually any organ in the
body.
 It affects principally the skin, kidneys, serosal membranes, joints, and
heart.
 Immunologically, the disease is associated with an enormous array of
autoantibodies, classically including antinuclear antibodies (ANAs).
 The clinical presentation of SLE is so variable, with so many
overlapping features with those of other autoimmune diseases (RA,
polymyositis, and others),

28. PATHOGENESIS of SLE
 The fundamental defect in SLE is a failure to maintain self tolerance,
leading to the production of a large number of autoantibodies that can
damage tissues either directly or in the form of immune complex deposits.
 The pathogenesis of SLE involves a combination of genetic and
environmental factors.
 Genetic susceptibility and exposure result in failure of self-tolerance and
persistence of nuclear antigens.
 Autoantibodies serve to internalize nuclear components, which engage
TLRs and stimulate IFN production.
 IFN may stimulate B and T cell responses to the nuclear antigens.

29. PATHOGENESIS of SLE
Genetic Factors
 Familial association
 Family members have an increased risk for the development of SLE.
 Up to 20% of clinically unaffected first-degree relatives may have autoantibodies.
 Monozygotic twins (25%) > Dizygotic twins (1-3%)
 HLA association.
 The odds ratio (relative risk) for persons with HLA-DR2 or HLA-DR3 is 2 to 3, and if
both haplotypes are present, the risk is about 5.
 Other genes.
 Genetic deficiencies of classical pathway complement proteins, especially C1q, C2,
or C4, are seen in about 10% of patients with SLE.

30. PATHOGENESIS of SLE
Environmental Factors.
 Ultraviolet (UV) radiation (sun exposure) exacerbates the lesions of SLE -->
causes apoptosis of host cells,leading to an increased burden of nuclear
fragments and inflammatory responses to the products of dead cells.
 Cigarette smoking has been shown to be associated with the development of
SLE.
 Sex hormones had been thought to exert an important influence on the
development of disease.
 Drugs such as procainamide and hydralazine can induce an SLE-like disease, by
cause demethylation of DNA.

34. Immunologic Abnormalities in SLE.
 Type I interferons.
Blood cells show a striking molecular signature that indicates exposure to
interferon-α (IFN-α), a type I interferon that is produced mainly by
plasmacytoid DCs.
 TLR signals.
Studies in animal models have shown that TLRs that recognize DNA and RNA,
notably the DNA recognizing TLR9 and the RNA-recognizing TLR7, produce
signals that activate B cells specific for self nuclear antigens.
 Failure of B cell tolerance.
Studies with B cells from patients with SLE suggest the presence of defects in
both central and peripheral tolerance, resulting in a higher frequency of
autoreactive B cells than that typical for healthy people.

35. Spectrum of Autoantibodies in SLE

36. LE CELL PHENOMENON
 First diagnostic laboratory test described for
SLE.
 Principle :ANAs cannot penetrate the intact
cells and thus cell nuclei should be exposed to
bind them with the ANAs resulting in
homogeneous mass of nuclear chromatin
material.
 LE cell is a phagocytic leucocyte, commonly
poly morphonuclear neutrophil, and
sometimes a monocyte, which engulfs the
homogeneous nuclear material of the injured
cell.
Two LE cells having rounded
masses of amorphous nuclear
material (LE body) which has
displaced the lobes of neutrophil
to the rim of the cell.

37. Morphology of major lesions in SLE
 Blood Vessels.
An acute necrotizing vasculitis affecting small arteries and arterioles may be
present in any tissue.
 Kidneys.
Diffuse lupus nephritis (class IV) is the most serious form of renal lesions in
SLE and is also the most commonly encountered in renal biopsies, occurring in
35% to 60% of patients.
 Skin Lesions
 A characteristic erythematous or maculopapular eruption over the malar
eminences and bridge of the nose (“butterfly pattern”) is observed in
approximately half of the cases.
 Exposure to sunlight (UV light) exacerbates the erythema (so-called
photosensitivity), and a similar rash may be present elsewhere on the
extremities and trunk.

39. Lupus nephritis
Lupus nephritis showing a glomerulus
with several “wire loop” lesions
representing extensive subendothelial
deposits of immune complexes (periodic
acid Schiff stain)
Deposition of IgG antibody in a
granular pattern, detected by
immunofluorescence.

40. Histopathology of skin lesions in SLE
An H&E-stained section shows
liquefactive degeneration of the basal
layer of the epidermis and edema at the
dermoepidermal junction.
An immunofluorescence micrograph
stained for IgG reveals deposits of
immunoglobulin along the
dermoepidermal junction.

41. Hashimoto’s Thyroiditis
Immune destruction of thyroid cells
 An association of cytotoxic lymphocyte-associated antigen 4
(CTLA4), a T cell regulatory gene, with autoimmune
phenomenon in Hashimoto’s disease has been reported.
 There is initial activation of CD4+ T helper cells, which then
induce infiltration of CD8+ T cytotoxic cells in the thyroid
parenchyma.
 In the process, B cells are also activated to form autoantibodies,
which bring about immune destruction of thyroid parenchyma.

42. Hashimoto’s Thyroiditis
The following autoantibodies against different thyroid cell
antigens are detectable in the sera of most patients with
Hashimoto’s thyroiditis:
i. Thyroid microsomal autoantibodies (against the
microsomes of the follicular cells).
ii. Thyroglobulin autoantibodies.
iii. TSH receptor autoantibodies.
iv. Less constantly found are thyroid autoantibodies against
follicular cell membranes, thyroid hormones themselves
and colloid component other than thyroglobulin.

43. Hashimoto’s Thyroiditis
There is lymphoid cell infiltration with formation of lymphoid follicles having
germinalcentres; small, atrophic and colloid-deficient follicles; presence of
Hurthle cells which have granular oxyphil cytoplasm and large irregular nuclei;
andslight fibrous thickening of lobular septa.

44. Grave’s Disease
Genetic factors.
 A familial occurrence has been observed.
 Susceptibility to develop Graves’ disease has been found associated with HLA-
DR3(Hashimoto’s thyroiditis has both HLA-DR3 and HLA-DR5 association,
CTLA-4 and PTPN22 (a T-cell regulatory gene).
Autoimmune disease association
 Graves’ disease and Hashimoto’s thyroiditis are frequently present in the same
families and the two diseases may coexist in the same patient.

45. •Production of thyroid hormones is
regulated by thyroid-stimulating
hormones (TSH)
•The binding of TSH to a receptor on
thyroid cells activates adenylate cyclase
and stimulates the synthesis of two
thyroid hormones: thyroxine and
triiodothyronine
•A person with Grave’s Disease makes
auto-antibodies to the receptor for TSH.
The binding of these auto-antibodies to
the receptor mimics the normal action
of TSH, without the regulation, leading
to overstimulation of the thyroid
•The auto-antibodies are called long-
acting thyroid stimulating hormones
Grave’s Disease

46. Grave’s Disease
Autoantibodies
 TSH-receptor autoantigen is the main antigen against which autoantibodies are
directed. These are as under:
i) Thyroid-stimulating immunoglobulin (TSI):
It binds to TSH receptor and stimulates increased release of thyroid hormone.
ii) Thyroid growth-stimulating immunoglobulins (TGI):
It stimulates proliferation of follicular epithelium.
iii) TSH-binding inhibitor immunoglobulins (TBII):
It is inhibitory to binding of TSH to its own receptor.
Depending upon its action as inhibitory or stimulatory to follicular
epithelium, it may result in alternate episodes of hypo- and hyperthyroidism.

47. Grave’s Disease
The follicles are small and are lined by tall columnar epithelium,
which is piled up at places forming papillary infoldings.
Colloid is nearly absent and appears lightly staining, watery
and finely vacuolated.

48. Rheumatoid Arthritis
 Rheumatoid arthritis (RA) is a systemic, chronic inflammatory
autoimmune disease affecting many tissues but principally attacking the
joints.
 It causes a nonsuppurative proliferative synovitis that frequently progresses
to destroy articular cartilage and underlying bone with resulting disabling
arthritis.
 The pathologic changes are caused mainly by cytokine-mediated
inflammation, with CD4+ T cells being the principal source of the
cytokines.
 Many patients also produce antibodies against cyclic citrullinated
peptides (CCPs)

49. Pathogenesis of Rheumatoid Arthritis

50. Rheumatoid Arthritis
Immunologic derangements
1. Detection of circulating autoantibody called rheumatoid factor (RF)
against Fc portion of autologous IgG in about 80% cases of RA.
2. The presence of antigen-antibody complexes (IgG-RF complexes) in
the circulation as well as in the synovial fluid.
3. The presence of other autoantibodies such as antinuclear factor (ANF),
antibodies to collagen type II, and antibodies to cytoskeleton.
4. Antigenicity of proteoglycans of human articular cartilage.
5. The presence of g-globulin, particularly IgG and IgM, in the
6. synovial fluid.
7. Association of RA with amyloidosis.
8. Activation of cell-mediated immunity as observed by presence of
numerous inflammatory cells in the synovium, chiefly CD4+ T
lymphocytes and some macrophages.

51. •RA involves first the small joints of hands and feet and then symmetrically
affects the joints of wrists, elbows, ankles and knees.
•The proximal interphalangeal and metacarpophalangeal joints are affected
most severely.
•Frequently cervical spine is involved,but lumbar spine is spared.

52. The characteristic histologic features are villous hypertrophy of the synovium
and marked mononuclear inflammatory cell infiltrate in synovial membrane
with formation of lymphoid follicles at places.

53. Sjogern Syndrome
 Sjögren syndrome is a
clinicopathologic entity
characterized by dry eyes
(keratoconjunctivitis sicca) and
dry mouth (xerostomia),
resulting from immune-
mediated destruction of the
lacrimal and salivary glands.
 Occurs as an isolated disorder
(primary form), also known as
the sicca syndrome, or more
often in association with another
autoimmune disease (secondary
form).

54. Pathogenesis of Sjogern Syndrome
 Autoimmune disease caused by CD4+ T cell reactions against unknown
antigens in the ductal epithelial cells of the exocrine glands.
 Systemic B cell hyperactivity, as evidenced by the presence of ANAs
and rheumatoid factor (RF) (even in the absence of associated RA).
 Most patients with primary Sjögren syndrome have autoantibodies to
the ribonucleoprotein (RNP) antigens SS-A (Ro) and SS-B (La) - not
specific.
 Genetic variables like inheritance of certain class II MHC alleles.

55. Histopathology in Sjogern Syndrome
Histopathologic findings include intense lymphocytic and
plasma cell infiltration with ductal epithelial hyperplasia.

56. PERNICIOUS ANAEMIA
 Chronic disorder of middle-aged and elderly individual of either sex in
which intrinsic factor (IF) secretion ceases owing to atrophy of the
gastric mucosa.
 The most characteristic pathologic finding in PA is gastric atrophy
affecting the acid and pepsin-secreting portion of the stomach and
sparing the antrum.
 Gastric epithelium may show cellular atypia.
 About 2-3% cases of PA develop carcinoma of the stomach.

57. PERNICIOUS ANAEMIA
 The incidence is high in patients with other autoimmune diseases such as
Graves’ disease, myxoedema, thyroiditis, vitiligo, diabetes and idiopathic
adrenocortical insufficiency.
 Patients have anti-parietal cell antibody (90% cases) and antiintrinsic
factor antibody (50% cases).
 Relatives of patients with PA have an increased incidence of the disease or
increased presence of autoantibodies.
 Corticosteroids have been reported to be beneficial in curing the disease both
pathologically and clinically.
 PA is more common in patients with agammaglobulinaemia supporting the
role of cellular immune system in destruction of parietal cells.
 Certain HLA types have been reported to be associated with PA.

58. PERNICIOUS ANAEMIA
Chronic atrophic gastritis (right)
There is marked gastric atrophy with
disappearance of gastric glands and
appearance of goblet cells (intestinal
metaplasia)
Chronic atrophic gastritis with
intestinal metaplasia.

59. Autoimmune Haemolytic Anaemia
(AIHA)
 Autoimmune haemolytic anaemia (AIHA) characterised by formation
of autoantibodies against patient’s own red cells.
 Depending upon the reactivity of autoantibody, AIHA is further
divided into 2 types:
1. ‘Warm’ antibody AIHA in which the autoantibodies are reactive at body
temperature (37°C).
2. ‘Cold’ antibody AIHA in which the autoantibodies reactbetter with
patient’s own red cells at 4°C.

60. Autoimmune Haemolytic Anaemia
(AIHA)
‘WARM’ ANTIBODY AIHA
 Warm antibodies reactive at body temperature and coating the red cells are
generally IgG class antibodies and occasionally IgA.
 Human red cells coated with IgG antibodies are bound to the surface of RE
cells, especially splenic macrophages.
 Red cells coated with IgG along with C3 on the surface further promote this
red cell-leucocyte interaction, accounting for more severe haemolysis.
 The spleen traps and destroys these red cells coated with IgG antibodies.
 Positive direct Coombs’ (antiglobulin) test for presence of warm antibodies
on the red cell, best detected at 37°C.
 A positive indirect Coombs’ (antiglobulin) test at 37°C may indicate
presence of large quantities of warm antibodies in the serum.

61. Autoimmune Haemolytic Anaemia
(AIHA)
‘COLD’ ANTIBODY AIHA
 The antibodies are IgM type which bind to the red cells best at 4°C.
 These cold antibodies are usually directed against the I antigen on the red
cell surface.
 Agglutination of red blood cells by IgM cold agglutinins is most profound
at very low temperature.
 Haemolytic effect is mediated through fixation of C3 to the red blood cell
surface and not by agglutination alone.
 It is seen in the course of certain infections (e.g. Mycoplasma Pneumonia,
infectious mononucleosis) and in lymphomas.
 Positive direct Coombs’ test for detection of C3 on the red cell surface but
IgM responsible for C3 coating on red cells is not found.

62. TYPE 1 DIABETES MELLITUS
 Type 1 diabetes is an autoimmune disease in which islet destruction is
caused primarily by immune effector cells reacting against endogenous
beta cell antigens.
 The fundamental immune abnormality in type 1 diabetes is a
failure of self-tolerance in T cells.
 The principal susceptibility locus for type 1 diabetes resides in
the chromosomal region that encodes the class II MHC
molecules on 6p21 (HLA-D).
 Environmental factors, especially infections caused by certain
viruses (mumps, rubella, and coxsackie B viruses, in particular) may be
an initiating trigger, perhaps because some viral antigens are
antigenically similar to beta cell antigens (molecular mimicry)

63. Pathogenesis of Type 1 Diabetes Mellitus
 Autoimmune attack directed against specialized insulin-producing cells (beta cells)
that are located in spherical clusters, called the islets of Langerhans,scattered
throughout the pancreas.
 Activated CTLs migrate into an islet and begin to attack the insulin producing cells,
causing insulitis.
 This is is followed by cytokine (IFN-γ, TNF- α and IL-1) release and the presence of
auto-antibodies, which leads to a cell-mediated DTH response.
 The subsequent beta-cell destruction is thought to be mediated by cytokines
released during the DTH response and by lytic enzymes released from the activated
macrophages.

64. islet of Langerhans (a) in
pancreas from a normal mouse
(b) one in pancreas from a
mouse with a disease
resembling insulin-dependent
diabetes mellitus

65. MYASTHENIA GRAVIS
 Neuromuscular disorder of autoimmune origin in which the
acetylcholine receptors (AChR) in the motor end-plates of the muscles
are damaged.
 Presents clinically with muscular weakness and fatiguability, initially in
the ocular musculature but later spreads to involve the trunk and
limbs.
 10% mortality due to severe generalised disease and involvement of
respiratory muscles.
 Other autoimmune diseases have been found associated with MG such
as autoimmune thyroiditis, rheumatoid arthritis, SLE, pernicious
anaemia and collagen-vascular diseases.

66. MYASTHENIA GRAVIS
 The basic defect is reduction in the number of available AChRs at the
postsynaptic muscle membrane.
 These changes result in decreased neuromuscular transmission leading
to failure to trigger muscle action potentials and consequent weakened
muscle contraction.
 About 85-90% patients have anti-AChR-antibodies in their sera which
reduce the number of available AChRs by
 blocking the active sites of the receptors .
or
 damaging the post-synaptic muscle membrane in collaboration with complement.
 Majority of patients may have either thymoma or thymic hyperplasia.
 The thymus possibly sensitises B cells to produce anti-AChR
antibodies.

67. MYASTHENIA GRAVIS
Light microscopy
 a few clumps of lymphocytes may be found around small blood
vessels.
 Degenerating muscle fibres are present in half the cases.
 Electron microscopy
 Reduction in synaptic area of the motor axons due to flattening or
simplification of postsynaptic folds.
 The number of AChRs is greatly reduced.
 It is possible to demonstrate the complex of IgG and complement at the
neuromuscular junctions by combination with immunocytochemistry

68. MULTIPLE SCLEROSIS
 An autoimmune demyelinating disorder characterized by distinct
episodes of neurologic deficits, separated in time, attributable to white
matter lesions that are separated in space.
 Women are affected twice as often as men.
 Caused by a combination of environmental and genetic factors that
result in a loss of tolerance to myelin antigen.
 A significant fraction of the genetic risk for MS is attributable to HLA-
DR variants, the DR2 allele being the one that most significantly
increases the risk for developing MS.
 A central role for CD4+ T cells has been suggested, with an increase in
TH17 and TH1 CD4+ cells thought to be a critical component of the
injury to myelin.

69. MULTIPLE SCLEROSIS
 Affected areas shows multiple, well-circumscribed, slightly depressed,
glassy-appearing, gray-tan, irregularly shaped lesions termed plaques.
 In an active plaque there is evidence of ongoing myelin breakdown
with abundant macrophages containing myelin debris.
 Active plaques fall into four classes:
 Type I, which has macrophage infiltrates with sharp margins
 Type II, which is type I + complement deposition.
 Type III, with less well-defined borders and oligodendrocyte apoptosis.
 Type IV, with nonapoptotic oligodendrocyte loss.
 In inactive plaques, the inflammation mostly disappears, leaving behind
little to no myelin.

70. Section of fresh brain showing
a plaque around occipital horn of
the lateral ventricle.
Unstained regions of demyelination
(MS plaques) around the fourth
ventricle.
Luxol fast blue–periodic acid–Schiff
stain for myelin

71. MULTIPLE SCLEROSIS
 The CSF in patients with MS shows a mildly elevated protein level with
an increased proportion of immunoglobulin and moderate pleocytosis.
 When the immunoglobulin is examined further, oligoclonal bands
usually are identified.
 Although B cells are clearly involved in the pathogenesis, the
contribution of these characteristic antibodies to the disease process is
unknown.

72. SUMMARY
 Autoimmunity - Breakdown in self-tolerance.
 Muliple causes - genetic, environmental, nutrition,
infections, etc
 Organ specific or Systemic.
 Majority are caused by autoAb production
 Treatment: Immunosuppressive drugs, Abs against
TCR, cytokines, adhesion molecules, etc.

73. References
 Robbins and Cotran Pathologic Basis of Disease 9th edition.
 Harsh Mohan Textbook of Pathology, 7th edition.
 Kuby Immunology 5th edition.
 Yamamoto K Mechanisms of Autoimmunity, the Journal of the Japan Medical
Association Vol. 129, No. 7, 2003, pages 895–898

74. THANK YOU