MECHANISMS OF AUTOIMMUNITY

&
SYSTEMIC LUPUS ERYTHEMATOSUS
Dr Rashmi Gautam
Competency:

• PA9.5 Define and describe the pathogenesis of systemic Lupus

Erythematosus
AUTOIMMUNITY
• Immune reactions against self-antigens—autoimmunity
• categorized as autoimmune if it meets the following 3 requirements:
the presence of an immune reaction specific for some self antigen or self tissue
evidence that such a reaction is not secondary to tissue damage but is of primary
pathogenic significance
the absence of another well-defined cause of the disease
Autoimmune diseases
Organ-Specific Systemic
Diseases Mediated by Antibodies
Autoimmune hemolytic anemia Systemic lupus erythematosus
Autoimmune thrombocytopenia
Autoimmune atrophic gastritis (pernicious anemia)
Myasthenia gravis
Graves disease
Goodpasture syndrome

Diseases Mediated by T Cells

Type 1 diabetes mellitus Rheumatoid arthritis
Multiple sclerosis Systemic sclerosis (scleroderma)
Sjögren syndrome

Diseases Postulated to Be Autoimmune

Inflammatory bowel diseases (Crohn disease, ulcerative colitis) Polyarteritis nodosa
Primary biliary cirrhosis Inflammatory myopathies
Autoimmune (chronic active) hepatitis
Immunologic Tolerance

• Immunologic tolerance is the phenomenon of unresponsiveness to an antigen

induced by exposure of lymphocytes to that antigen
• Self-tolerance refers to a lack of responsiveness to an individual’s antigens
• Underlies our ability to live in harmony with our cells and tissues

• Breakdown of tolerance is the basis of autoimmune diseases

Immunologic Tolerance

Immunological-tolerance

Peripheral tolerance
Central tolerance

Thymus Bone Marrow • Anergy/unresponsiveness

• Clonal deletion by Apoptosis
T cells B cells • T-regulatory cells
• Antigen sequestration
• Negative selection or clonal deletion
• Receptor editing
Central tolerance:
• Immature lymphocytes that recognize self-antigens during maturation in the
central lymphoid organs are killed or rendered harmless.

developing lymphocytes

random somatic antigen receptor gene rearrangements

diverse antigen receptors

may have high affinity for self antigens

• The mechanisms of central tolerance eliminate these potentially dangerous
lymphocytes by negative selection/ clonal deletion or receptor editing
Negative selection or clonal deletion

(Thymus)

immature T cells expressing TCRs specific for self antigens

encounter self-antigens in the thymus

signals

Apoptosis

killing of self reactive T cells

Receptor editing
(Bone Marrow)

developing B cells

recognize self-antigens

reactivate the machinery of antigen receptor gene rearrangement

express new antigen receptors, not specific for self antigens

• ¼ to ½ of all B cells in the body may have undergone receptor editing during
their maturation
• If receptor editing does not occur, the self-reactive cells undergo apoptosis,
thus purging potentially dangerous lymphocytes from the mature pool
• Central tolerance, however, is imperfect
• Not all self-antigens may be present in the thymus and bone marrow
• Lymphocytes bearing receptors for such autoantigens escape into the
periphery
• Can inflict tissue injury
• Unless they are deleted or muzzled in the peripheral tissues
Peripheral tolerance: best defined for T cells

mature lymphocytes that recognize self antigens in

peripheral tissues

functionally suppression by Antigen Clonal

inactive regulatory sequestration deletion
(clonal T lymphocytes apoptosis
anergy)
Anergy
• Phenomena by which lymphocytes that
recognize self-antigens are rendered
functionally unresponsive
• Activation of antigen-specific T cells
requires two signals:
 recognition of peptide antigen in association
with self MHC molecules on the surface of
APCs
 set of costimulatory signals (“second
signals”) from APCs
• second signals- T cell–associated
molecules, such as CD28, that bind to
their ligands on APCs
• If the antigen is presented to T cells without adequate levels of costimulators,
the cells become anergic.
• Because costimulatory molecules are not expressed or are weakly expressed
on resting DCs in normal tissues, the encounter between autoreactive T cells
and their specific self antigens displayed by these DCs may lead to anergy
Suppression by regulatory T cells
• A population of T cells called regulatory T cells functions to prevent immune
reactions against self antigens.
• Regulatory T cells develop mainly in the thymus and may also be induced in
peripheral lymphoid tissues.
• The best-defined regulatory T cells are CD4+ cells that express high levels of
CD25
• They suppress immune responses by the secretion of immunosuppressive
cytokines such as IL-10 and TGF-β, which inhibit lymphocyte activation and
effector functions
• Also prevent immune response against the fetus and commensal microbes
Deletion by apoptosis
• T cells that recognize self antigens receive signals that promote their death by
apoptosis.
• Occurs in thymus and the periphery.
• Two mechanisms
 express a pro-apoptotic member of the Bcl family, called Bim, without antiapoptotic
members of the family like Bcl-2 and Bcl-xl; Unopposed Bim triggers apoptosis by the
mitochondrial pathway
 Fas-Fas ligand system.
Antigen sequestration
• Passive immune tolerance
• Occurs when antigens are kept away from the immune system by anatomic
and physiologic barriers. Eg. in eye, brain, and testis
• “Immunologically privileged sites" because it's difficult to trigger an immune
response to antigens in them.
• Antigens can be sequestered by: blood-brain barrier, lack of lymphatic
drainage, and a limited ability to express MHC molecules
• Sequestered Ag when released into the circulation (trauma or infection) cause
a severe immune response because it activates self-reactive lymphocytes
Immunologic Tolerance
Mechanism of autoimmunity
The factors that lead to a failure of self-
tolerance and the development of
autoimmunity include:
1. Inheritance of susceptibility genes-
contribute to the breakdown of self-
tolerance
2. Environmental triggers
• Infections
• Tissue damage
promote the activation of self-reactive
lymphocytes
Mechanism of autoimmunity
the following abnormalities appear to contribute to its development:
• Defective tolerance or regulation
• Abnormal display of self antigens
 increased expression and persistence of self-antigens that are normally
cleared
 “Neoantigens” (new epitopes that are not expressed normally), the
immune system may not be tolerant to these epitopes, and anti-self
responses may develop
 Neoantigens are structural changes in these antigens resulting from
posttranslational enzymatic modifications or from cellular stress or injury
• Inflammation- Microbes or cell injury may elicit local inflammatory
reactions that may be triggers for subsequent autoimmunity
Role of Susceptibility Genes
• Autoimmunity has a genetic component
incidence of the disease is greater in twins of affected individuals than in the
general population, and greater in monozygotic than in dizygotic twins
• Most autoimmune diseases are complex multigenic disorders
Association of HLA Alleles With Disease

• The strongest group of

genes that
associates with
autoimmunity
• The most striking
association is seen between
ankylosing spondylitis and
HLA-B27; (100- to 200-
fold greater chance)

• HLA allele is not, by itself,

the cause of the disease
Polyphormism in Non- MHC genes
• Associated with various
autoimmune diseases and
may contribute to failure
of self- tolerance or
abnormal
activation of lymphocytes

• These in combination
with environmental
factors induce the
immunologic
abnormalities that lead
to autoimmunity

• Epigenetic changes also

affect the diseases onset
Association of Non-MHC Genes With Autoimmune Disease
Three recently described genetic associations are especially interesting
• Polymorphisms in a gene called PTPN22, which encodes a protein tyrosine
phosphatase, are associated with rheumatoid arthritis, type 1 diabetes
• Polymorphisms in the gene for NOD2 are associated with Crohn disease
• Polymorphisms in the gene encoding the IL-2 receptor (CD25) are
associated with multiple sclerosis
Role of Infections and Other Environmental Influences
• Infections may trigger autoimmune reactions
• Two mechanisms
 Bystander activation:
 Molecular mimicry
• infections upregulate the
• Some microbes express antigens that have the
expression of costimulators on
same amino acid sequences as self-antigens
APCs
• Immune responses against the microbial
• If these cells are presenting
antigens may result in the activation of self-
self-antigens, the result is
reactive lymphocytes
breakdown of anergy and
• Ex. Rheumatic heart disease, in which
activation of T cells specific
antibodies against streptococcal proteins
for the self-antigens
cross-react with myocardial proteins and
cause myocarditis
Microbes induced other abnormalities
• Some viruses (EBV and HIV) cause polyclonal B-cell activation, which may
result in production of autoantibodies
• The tissue injury in infections may release and structurally modify self
antigens, creating neoantigens that are able to activate T cells
• Infections may induce the production of cytokines that recruit lymphocytes,
including potentially self-reactive lymphocytes, to sites of self antigens
Other contributors:
• Display of tissue antigens also may be altered by a variety of environmental
insults
• UV radiation → cell death → exposure of nuclear antigens → pathologic
immune responses (lupus flares with exposure to sunlight)
• Smoking (risk factor for rheumatoid arthritis), leads to chemical
modification of self antigens
• Anatomic alterations in tissues, caused by inflammation (possibly secondary
to infections), ischemic injury, or trauma, may lead to the exposure of self
antigens that are normally concealed from the immune system
• Strong gender bias, more
common in women
1. effects of hormones
2. unknown genes on the X
chromosome
SYSTEMIC LUPUS ERYTHEMATOSUS
Systemic Lupus Erythematosus
• An autoimmune disease involving multiple organs, characterized by a vast
array of autoantibodies, antinuclear antibodies (ANAs), in which injury is
caused mainly by deposition of immune complexes and binding of
antibodies to various cells and tissues
• Over 40 different genes predispose to SLE
• Characterized by remissions and exacerbations

Organs most commonly affected:

Heart, joints, skin, lungs, blood vessels, liver, kidney and central nervous system
Systemic Lupus Erythematosus
• Common disease with Prevalence as high as 1 in 2500 in certain
populations.
• Affects women (1 in 700 among women of childbearing age and a female-
to-male ratio of 9: 1 in the reproductive age group of 17 to 55 years)
• Most often presents in the twenties and thirties
• Twofold to threefold higher prevalence in blacks and Hispanics than in
whites
• Acute or insidious in onset
• Chronic remitting relapsing illness
Etiology
• Currently unknown but genetic and environmental factors are involved

Environmental Factors
• Exposure to ultraviolet (UV) light
• Alfa-alfa sprouts
• Actions of sex hormones
• Drugs: hydralazine, procainamide, D-penicillamine
• Infections: Parvovirus, HCV, CMV
Pathogenesis
• The fundamental defect is failure of the mechanisms that maintain self-
tolerance.
• Both genetic and environmental factors play a role.
• Genetic Factors
 Genetically complex disease with contributions from MHC and multiple non-MHC
genes.
 Family members of patients have an increased risk of developing SLE
 20% of clinically unaffected first-degree relatives of SLE patients have autoantibodies
and other immune abnormalities
 higher rate of concordance (>20%) in monozygotic twins when compared with
dizygotic twins (1% to 3%).
Genetic factors
 HLA associations support the concept that MHC genes regulate production of
particular autoantibodies
 alleles of the HLA-DQ locus have been linked to the production of anti–double-
stranded DNA, anti-Sm, and antiphospholipid antibodies, although the relative risk is
small.
 Some patients have inherited deficiencies of early complement components, C2, C4,
or C1q
 Deficiency of C1q results in defective phagocytic clearance of apoptotic cells
 Many cells normally undergo apoptosis, and if they are not cleared their nuclear
components may elicit immune responses.
 Several genetic loci encode proteins involved in lymphocyte signaling and interferon
responses, both of which may play a role in lupus pathogenesis,
 Immunologic Factors
 Failure of self-tolerance in B cells
 Activation of CD4+ helper T cells specific for nucleosomal antigens that escape
tolerance and help B cells to produce high-affinity pathogenic autoantibodies
 TLR engagement by nuclear DNA and RNA contained in immune complexes may
activate B lymphocytes
 Type I interferons play a role in lymphocyte activation in SLE
Environmental Factors
• Exposure to ultraviolet (UV) light induces apoptosis in cells and may alter
the DNA so that its recognition by TLRs is enhanced
• UV light may modulate the immune response, for example, by stimulating
keratinocytes to produce IL-1, a cytokine known to promote inflammation
• The gender bias of SLE is partly attributable to actions of sex hormones and
unknown genes on the X chromosome
• Drugs such as hydralazine, procainamide, and penicillamine can induce an
SLE-like response in humans
Pathogenesis:
Mechanisms of Tissue Injury
• Different autoantibodies are the cause of most of the lesions of SLE
• Immune complex deposits (type III hypersensitivity).
 Low levels of serum complement (secondary to consumption of complement proteins)
 Granular deposits of complement and immunoglobulins in the glomeruli further
support the role of immune complex deposition
 T-cell infiltrates
• Autoantibodies specific for red blood cells, white blood cells, and platelets opsonize these
cells and promote their phagocytosis and destruction, resulting in cytopenias (antibody-
mediated (type II) hypersensitivity.
• Antiphospholipid antibody syndrome. The mechanisms of thrombosis are not defined, and
antibodies against clotting factors, platelets, and endothelial cells have all been proposed
as being responsible for thrombosis
• The neuropsychiatric manifestations- antibodies that cross the blood-brain barrier and
react with neurons or receptors for various neurotransmitters
• Cytokines
Clinical Features
• Multisystem disease with highly
variable presentation
• Acute or insidious in its onset
 young woman
 butterfly rash over the face
 Fever
 Pain but no deformity in one or
more peripheral joints (feet, ankles,
knees, hips, fingers, wrists, elbows,
shoulders)
 Pleuritic chest pain
 Photosensitivity
Clinical Features
• Hematuria, red cell casts, proteinuria, and in some cases the classic nephrotic
syndrome- Renal involvement
• Hematologic derangements like anemia or thrombocytopenia may be the
presenting manifestation
• Mental aberrations, including psychosis or convulsions, or coronary artery
disease may be prominent.
• Prone to infection-underlying immune dysfunction and treatment with
immunosuppressive drugs
 Lupus Percarditis Dermatitis – sun exposed areas
Malar “butterfly” Rash
SLE

Gangrene of the toe

Due to vasculitis Joint Swelling Lupus Nephritis
Clinical & Pathological Manifestations
Clinical manifestation Prevalence %
Haematologic 100
Arthritis 80-90
Skin 85
Fever 55-85
Fatigue 80-100
Weight loss 60
Renal 50-70
CNS 25-35
Pleuritis 45
Myalgia 33
Pericarditis 25
GI 20
Raynaud 15-40
Ocular 5-15
Peripheral neuropathy 15
SLE – Laboratory features

• Anemia, thrombocytopenia, leukopenia (class II reaction)

• ESR elevated; non-specific
• Elevated creatinine- lupus nephritis
• CPK- elevated in lupus myositis
• Urinalysis- glomerulonephritis with proteinuria with or without hematuria
• Anti-nuclear antibody (ANA)
• Anti- ds DNA antibody (virtually pathognomonic)
• Numerous other auto-antibodies (often lead to a false-positive test for
syphilis)
• Renal biopsy often shows glomerulonephritis
Spectrum of Autoantibodies in SLE

• Hallmark of SLE: production of autoantibodies

• Antibodies to double-stranded DNA and Smith [Sm] antigen are virtually
diagnostic
• These autoantibodies are pathogenic, either by
 forming immune complexes
 attacking their target cells
• Levels of these autoantibodies in the blood aid in diagnosis and
management of patients with SLE
ANA are directed against nuclear antigen

• Grouped into four categories based on their specificity for:

1. DNA
2. Histones
3. Nonhistone proteins bound to RNA
4. Nucleolar antigens
• ANAs are detected by indirect immunofluorescence.
• The pattern of nuclear fluorescence suggests the type of antibody present in
the patient’s serum
Four basic patterns
Homogeneous or diffuse chromatin, histones, and, double-
nuclear staining stranded DNA

Rim or peripheral staining antibodies to double-stranded

patterns DNA and sometimes to nuclear
envelope proteins

Speckled pattern non-DNA nuclear constituents

(most commonly and least such as Sm antigen,
specific pattern) ribonucleoprotein, and SS-A and
SS-B reactive antigens
Nucleolar pattern Antibodies to RNA

Centromeric pattern antibodies specific for

centromeres
ANA are directed against nuclear antigen
• Antibodies to dsDNA
 Rim or peripheral staining pattern with IF
 Highly specific for SLE
 Associated with active renal disease
• Antibodies to histones
 Homogeneous or diffuse staining with IF
 Particularly common in drug induced SLE
• Antibodies to non-histones proteins bound to RNA (Sm antigen, RNP, SS-A, SS-B etc.)
 Speckled pattern on IF; Sm antigen is specific for SLE; SS-B is associated with low
risk of nephritis; SS-A is seen in sabacute cutaneous LE; SS-A & SS-B are seen in
Sjogren’s
• Antibodies to nucleolar antigen
 A few discrete spots on IF; Specific for scleroderma
Specificity of autoantibody % positive Association with specific
disease features
Double-stranded DNA 40–60 Nephritis; specific for SLE

U1-RNP 30-40

Smith (Sm) antigen (core protein of small RNP 20-30 Specific for SLE
particles

Ro (SS-A)/La (SS-B) nucleoproteins 30–50 Congenital heart block (neonatal

lupus)
Phospholipid-protein complexes (anti-PL) 30-40 Antiphospholipid syndrome (in
~10% of SLE patients

Multiple nuclear antigens (“generic ANAs”) 95-100 Found in other autoimmune

diseases, not specific
• Diagnosis relies on a constellation of clinical, serologic, and
morphologic changes
A patient is classified as having SLE if four of the clinical and immunologic
criteria are present at any time (not necessarily concurrently), including at least
one clinical and one immunologic criterion
Morphology
• The most characteristic lesions result from immune complex deposition in
blood vessels, kidneys, connective tissue, and skin.

Blood Vessels
• Acute necrotizing vasculitis involving capillaries, small arteries, and
arterioles
• Arteritis- fibrinoid necrosis of the vessel walls
• Chronic stages- vessels undergo fibrous thickening with luminal narrowing
Kidney
• 50% patients have renal involvement: glomerulonephritis or tubulointerstitial
nephritis
• Glomerular lesions- deposition of immune complexes on the glomerular basement
membrane, in the mesangium, or throughout the glomerulus
• Six patterns:
 Minimal mesangial lupus nephritis (class I)
 Mesangial proliferative lupus nephritis (class II)
 Focal lupus nephritis (class III)
1. segmental (affecting only a portion of the glomerulus)
2. global (involving the entire glomerulus)
 Diffuse lupus nephritis (class IV)
 Membranous lupus nephritis (class V)
1. Segmental
2. global
 Advanced sclerosing lupus nephritis (class VI)
Kidney
Class IV lupus-
• Subendothelial immune complex
deposits may cause
circumferential thickening of the
capillary wall, forming “wire
loop” structures on light
microscopy
• Immune complexes can be readily
detected by electron microscopy
and immunofluorescence
• class I is the least common and
class IV is the most common
pattern.
Skin
• Rash on the face (butterfly rash), extremities and trunk
• Urticaria, bullae, maculopapular lesions, and ulcerations
also occur
• Exposure to sunlight incites or accentuates the erythema.
Microscopic:
• Vacuolar degeneration of the basal layer of the epidermis
• In the dermis- variable edema and perivascular
inflammation
• Vasculitis with fibrinoid necrosis may be prominent
• IF- deposition of immunoglobulin and complement along
the dermoepidermal junction
Lupus Dermatitis

Interface dermatitis with vacuolar

degeneration of basal cells

Granular deposition of IgG, IgA, IgM,

C3, and C1q along the basement
membrane
Cardiovascular System
• Involve any layer of the heart
• Pericardial involvement in 50% of patients
• Myocarditis less common
• Valvular abnormalities- mitral and aortic
valve -diffuse leaflet thickening- stenosis
and/or regurgitation
• Valvular endocarditis (called LibmanSacks
endocarditis)- single or multiple 1- to 3-mm
warty deposits on any heart valve,
distinctively on either surface of the leaflets
Spleen
• Splenomegaly, capsular thickening, and follicular hyperplasia
• Central penicilliary arteries may show concentric intimal and smooth muscle
cell hyperplasia, producing so-called onion-skin lesions
Lungs
• pleuritis and pleural effusion (50% of patients)
• chronic interstitial fibrosis- secondary pulmonary hypertension

• LE, or hematoxylin, bodies in the bone marrow or other organs are strongly
indicative of SLE
SLE – Clinical Course

• Extremely variable characterized by flare-ups and remissions

• 90% 5 year & 80% 10 year survival
• Treated with immunosuppression
• Causes of death
 Renal failure
 Infection
 Coronary artery disease
 Diffuse central nervous system involvement
SLE: Prognosis

• Usually chronic, relapsing and unpredictable.

• Remissions may last for years
• If initial acute phase is controlled (even if severe with cerebral thrombosis
or severe nephritis), prognosis is usually good
• The 10 year survival is > 95%
• Improvd prognosis in part is due to earlier diagnosis and more effective
therapies
• More severe disease requires more toxic therapies which increase the risk of
mortality
A 33 years old lady presented with photosensitivity, erythematous rash on
cheeks and nose, with oral ulcers. She had persistent proteinuria. Out of
various anti-nuclear antibodies, which is pathognomonic of this disease?
a) Antibody to single-stranded DNA
b) Antibody to double-stranded DNA
c) Antibody to histones
d) Antibody to nucleolar antigen
Types of SLE

Other autoimmune diseases

• Rheumatoid Arthritis
• Sjögren Syndrome
• Systemic Sclerosis (Scleroderma)
• IgG4-Related Disease
THANK YOU