Autoimmunity
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Transcript of Autoimmunity
ImmunityBy
G V Narasimha KumarAsst.Professor, Dept.of Pharmacology,
Sri Padmavathi school of Pharmacy
INTRODUCTION The role of the immune system is to keep the body healthy by
destroying that which it perceives to be non-self.
In Autoimmune Disease the body mistakes normal tissue for non-self and begins to attack the tissue in an attempt to destroy it.
Activation of an immune response against self-tissue
Specific breakdown of mechanisms responsible for tolerance to self-antigens
DEFINITION
Autoimmunity is a problem of self/non-self
discrimination.
Autoimmunity can be simply defined as loss of tolerance to self and is characterized by the production of lymphocytes or antibodies that are capable of reacting with self components. Autoimmune disease is a condition in which the natural unresponsiveness or tolerance to self terminates, as result of which antibody or sensitized lymphocyte is produced against self antigens, which reacts with self antigens causing disease.
The autoimmune response must be regularly associated with disease.
The antigen responsible for the immune response must be identified, isolated and
characterized.
Passive transfer of the disease must be possible by transfer of antibodies or sensitized
lymphocytes.A replica of the disease must be inducible in laboratory animals and immuno pathological
changes in the natural and experimental diseases should be parallel to each other.
CRITERIA FOR AUTO IMMUNE DISEASES
Witbesky’s Postulates
5 % to 7% adult affected.
Two third women.
More than 40 human diseases autoimmune in origin.
EPIDEMIOLOGY
HISTORY Horror autotoxicus
Literally, the horror of self-toxicity.
A term coined by the German immunologist Paul Ehrlich (1854-1915) to
describe the body's innate aversion to immunological self-destruction.
Ernest Witebsky (1950)- Demonstrated the induction of autoimmunity in an
animal model of chronic thyroiditis
PROPOSED MECHANISMS OF AUTOIMMUNITY
Proposed mechanisms for induction of Autoimmunity
Genetic abnormalities or
Mutations
Altered forms of self antigens
Or Neoantigens
Cross reactive or
shared antigens
Loss of Immunoregulation
Sequestered antigen
Loss of Tolerance
SEQUESTERED ANTIGEN / HIDDEN ANTIGEN
According to this theory, during embryonic development, tissues that are exposed to the lymphoreticular system are recognized as self antigens and, hence, are unable to induce immune response.
Late-developing antigens or those confined to specialized organs are not exposed to lymphoreticular system (e.g., testes, brain, eye, etc.).
Accidental traumatic injury or surgery exposes them to lymphoreticular system
Initiation of an autoimmune disease.
Ag released from hidden location
Many self Ag are found in hidden location eg. C N S ,TESTiS ,EYE (CORNEA)
Organ damage
Hidden Ag released
Reaches blood stream
Encounter Ag sensitive cells
Stimulate autoimmunity
Damage to immunologically privileged sites can lead to autoimmunity
CROSS REACTIVE ANTIGENS/ MOLECULAR MIMICRY
Sharing of epitopes between an infectious agent and its host.
Antibodies directed against the infectious agents starts reacting with normal self Ag.
Triggers autoimmunity.
MECHANISM OF CROSS REACTING OR SHARED ANTIGENSSome organisms carry antigenic
determinants
These antigens resemble host cell components known as
Cross – reacting antigens
Induce immune responses
Damage particular organs or tissues in the host
The following are the diseases that are caused due to cross
reactive antigens
Post Streptococcal nephritis and carditis (Rheumatic fever)
Anticardiolipin antibodies during syphilis
Association between Klebsiella and Ankylosing Spondylitis.
Molecular mimicry – homologous sequences are seen
Arthritogenic Shigella flexneri and HLA-B27
Mycobacterium tuberculosis and
Joint membranes, Coxsackie B and myocardium.
ALTERED FORMS OF SELF ANTIGENS OR NEO ANTIGENS
PHYSICAL(IRRADIATION)
CHEMICAL(DRUGS)
BIOLOGICAL( VIRAL
INFECTIONS )
Act on
Native tissue antigensUpon Antigenic alteration
Produce NeoantigensReact with antibodies
Cell injury
Mutations
LOSS OF IMMUNOREGULATION
The defect or lack of efficiency in the lymphoid cell population may result in loss of immunoregulation leading to loss of tolerance control.F
UNCTI
ONAL LOSS
Functional Loss of activity of both Th & Ts causing heightened antibody response.Self antigens behave like foreign antigen leading to autoimmune disease.
DEFECT I
N DEVELOPMENT
Defect in thymus in stem cell development & macrophage function may cause auto immune disease
STI
MULI
Non- specific polyclonal B cell activation by LipopolysaccharidesTrypsinNystatin Infections Like Mycoplasma, EB Virus, Malarial Parasite 2-mercaptoethanol
GENETIC FACTORS The important genes that regulate the development of autoimmunity
are located within MHC.
MHC have got critical role in maturation of T cell & induction of IR .
MHC ll genes are directly responsible for auto antigen processing and presentation.
The structure of Ag binding groove will determine , if specific Ag will trigger an AU response.
Eg. DIABETES MELLITUS IN DOG: DLA-A3, A7, A10 and DLA-B4
SLE: DLA- A7
POLYARTHRITIS: DLA- A7
LYMPHOCYTES ABNORMALITIES
Primary abnormalities either in B cell or T cell.
Since these cells are critical regulators of all IR.
MHC presentation of all antigenic peptide to these cells will be defective, in case the cells are abnormal.
Abnormalities in lymphocytes could affect any one of the mechanism that normally maintains self tolerance.
FAILURE OF CENTRAL TOLERENCE
• Inside primary lymphoid organ;
Positive selection
Negative selection (Deletion of self reacting T cells in thymus apoptosis).
• Failure of central tolerance starts AU diseases.
OCCUPATIONAL AND OTHER EXPOSURES ASSOCIATED WITH AUTOIMMUNE DISEASE
Exposure Disease
Silica Systemic sclerosis, SLE, RA
Solvents Systemic sclerosis, Multiple sclerosis, RA
Pesticides RA
UV radiation Multiple sclerosis, Dermatomyositis
Cigarette smoking RA, Autoimmune thyroid disease
INTERPLAYING FACTORS
AUTOIMMUNITY & LEFT-HANDEDNESS
Left handed individuals more affected.
11% of left handed & 4% of right handed.
Reasons for this are obscure.
Left-handedness & immune malfunction may both result from abnormal endocrine function in fetal life.
GENDER PREDOMINANCE IN AUTOIMMUNE DISEASES
1) Tissue destruction Diabetes: CTLs destroy insulin-producing b-cells in pancreas2) Antibodies block normal function
Myasthenia gravis: Ab binds acetylcholine receptors3) Antibodies stimulate inappropriate function Graves’ disease: Ab binds TSH receptor Mimics thyroid-stimulating
hormone activates unregulated thyroid hormone production4) Antigen-antibody complexes affect function Rheumatoid Arthritis: IgM specific for Fc portion of IgG IgM-IgG
complexes deposited in joints inflammation
EFFECTS OF AUTOIMMUNITY
Broadly classified into 4 groups 1. Haemolytic autoimmune diseases 2. Localized autoimmune diseases 3. Systemic autoimmune diseases 4. Transitory Diseases
CLASSIFICATION OF AUTOIMMUNE DISORDERS
Clinical disorder due to destructions of blood components. Auto Ab are formed against one’s own RBCs, Platelets or Leucocytes.
E.g.
Haemolytic anaemia
Thrombocytopenia
Leucopenia
HAEMOLYTIC AUTOIMMUNE DISEASES
Lysis of RBC is due to the production of autoantibodies against the RBC-antigens.
RBC half life = 21 days, Ha.anaemia<7days
Caused by 20 to infections or Drug therapy [PENICILLIN, Anti-hypertensive agent like METHYLDOPA results in destruction of RBCs]
Antibody mediated autoimmune diseases
2 classes of autoantibodies involved are:
IgM or Cold Agglutins- active at 40 C but not at 370C.
IgG or Warm Agglutins - active at 370 C but not at 40C.
AUTOIMMUNE HAEMOLYTIC ANEMIA
CLINICAL FEATURES
THROMBOCYTOPENIA
Characterized by low platelet count due to the production of antiplatelet Ab. (IgG type)
MECHANISM:
An interaction of Ab with bound drug or new Ag. causes intravascular agglutination of platelets & can be eliminated by phagocytic cells.
Antibody mediated autoimmune diseases.
PATHOPYSIOLOGY
LEUCOPENIA An example is lymphocytopenia in SLE and Rheumatoid arthritis
due to non agglutinating anti-leukocyte antibodies.
2. LOCALISED AUTOIMMUNE DISEASES Or
ORGAN SPECIFIC AUTOIMMUNE DISEASES
For example:
Thyroiditis
Multiple sclerosis
Myasthenia gravis
Type I Diabetes Mellitus
Graves’ Disease
Addison’s disease
Autoimmune orchitis
Autoimmune disease of the eye
Pernicious anemia
Autoimmune diseases of nervous system
A particular organ is affected due to auto Abs.
HASHIMOTO’S THYROIDITIS
Hashimoto's thyroiditis is a condition caused by inflammation of the thyroid gland.
It is the most common thyroid disease in the U.S.
Is characterized by the destruction of thyroid cells by various cell- and antibody-mediated immune processes.
Caused by auto Ab of IgG & IgM type against the constituents of thyroid gland
PATHOGENESIS Abs are specifically formed for thyroid perioxidase & thyroglobulin.
Abs interact with the enzyme
Development of inflammation in the thyroid gland
Thyroid gland is destroyed
Patient ultimately rendered hypothyroid (too little thyroid hormone)
Hashimoto Thyroiditis is Characterized by Goiters Enlarged thyroid gland Deficiency of TH (Thyroxin)
Graves’ disease (anti-thyroid stimulating hormone receptor {TSHR} antibodies)
GRAVES DISEASE
GRAVES’ DISEASE (ANTI-THYROID STIMULATING HORMONE; ANTI-TSH)
In Graves’ disease, the antibodies do not destroy the thyroid but act as if they are TSH (i.e., they bind and activate the TSH receptor)
COMPARISON OF HASHIMOTO’S THYROIDITIS & GRAVES DISEASE
MYASTHENIA GRAVIS
MG is a chronic autoimmune neuromuscular disease that affects
the myoneural junction that is characterized by varying degrees
of weakness of the skeletal (voluntary) muscles of the body.
Classified as a “B cell” Disease
Autoantibodies against nicotinic acetylcholine receptors
Myasthenia gravis is caused by a defect in the transmission of nerve impulses to muscles.
It occurs when normal communication between the nerve and muscle is interrupted at the neuromuscular junction - the place where nerve cells connect with the muscles they control.
Normally when impulses travel down the nerve, the nerve endings release a neurotransmitter substance, acetylcholine.
Acetylcholine travels through the neuromuscular junction and binds to acetylcholine receptors which are activated and generate a muscle contraction.
In myasthenia gravis, auto Abs block, alter, or destroy the receptors for acetylcholine at the neuromuscular junction which prevents the muscle contraction from occurring.
Diplopia (double vision)
Ptosis (drooping of eyelids)
Myasthenia gravis (anti-acetylcholine receptor
antibodies)
DIABETES MELLITUS TYPE 1 Insulin dependent diabetes mellitus (type 1) is an inflammatory
autoimmune disease of the pancreas, resulting in a lack of insulin.
Insulin is produced in the pancreas by beta cells of the islets of Langerhans. Insulin is necessary for glucose to get into cells and be used for energy production. After eating, the glucose level in blood rises, which leads to insulin being released from the pancreas.
In a person with type 1 diabetes mellitus, the beta cells of Langerhans are damaged by autoimmune inflammation, leading to an insufficiency of insulin. The glucose level in blood rises and cells do not have enough energy for metabolism.
Type 2 diabetes (non-insulin-dependent diabetes mellitus) Insulin
concentrations are mostly increased but peripheral tissues are
resistant to insulin (insulin resistance). Beta cells are not able
increase secretion of insulin to overcome this resistance. Type 2
diabetes usually develops after 40 years of age in overweight
people, lately in obese adolescents.
DIABETES MELLITUS TYPE 2
Immunobiology 6th Ed.
ADDISON’S DISEASE In this disease, there is lymphocytic infiltration of the adrenal glands and the
presence of circulating antibodies directed against the cells of zona glomerulosa.
Occurs mainly due to primary hypoadrenalism
CAUSES: Autoimmune diseases Tuberculosis Surgical removal Hemorrhage or infarction
Meningococcal Septicemia Venography
CLINCAL FEATURES
AUTOIMMUNE ORCHITISDEFINITION:
INFLAMMTION OF TESTIS is called as orchitis.
In this disease
Sperm agglutinating antibodies causing
aggregation of spermatozoa are produced.
These antibodies interfere with penetration
of sperms into cervical mucosa
Lymphocytic infiltration of testis and presence of circulating antibodies against the sperms and germinal cells can be demonstrated.
CAUSES: Urethritis
Cystitis
Prostatitis
Seminal vesiculitis
Genitourinary tuberculosis
Tuberculous seminal vesiculitis
Renal tuberculosis
Tuberculosis of lungs
CLINICAL FEATURES:
Firm, tense, swollen and congested testicle.
Congestion
oedema
Diffuse infiltration by Neutrophils, lymphocytes, macrophages, plasma cells of neutrophilic abcsess.
AUTOIMMUNE DISEASES OF THE EYE
PHACOANAPHYLAXIS
• Intra ocular inflammation due to autoimmune response to the lens protein following cataract surgery.
PERFORATING INJURIES OF EYE
• Injuries involving the iris or the ciliary bodies are followed by sympathetic opthalmia in the opposite eye.
PERNICIOUS ANEMIA
It is an autoimmune disorder in which there is atrophic gastritis
with loss of parietal cells in the gastric mucosa with consequent
failure of intrinsic factor production & vitamin B12 production.
It was first described by ADDISON in 1885 and hence also termed as Addisonian megaloblastic anemia.
ABNORMAL UTILISATION
Congenital transcobalamin II deficiency
Nitrous oxide(inactivates B12)
CAUSES
PATHOPHYSIOLOGY
CLINICAL FEATURES
AUTOIMMUNE DISEASES OF NERVOUS SYSTEM These include neuroparalytic accidents due to cross-reaction between
human and sheep brain antigens following rabies vaccination.
Idiopathic polyneuritis (GUILLIAN- BARRE SYNDROME) is considered to be an autoimmune response against peripheral nervous system.
GBS (GUILLIAN- BARRE SYNDROME): It is an autoimmune demyelinating disease of the neurons that occurs
due to infection resulting in polyneuropathy.
It is also called as acute inflammatory or post infective neuropathy, acute inflammatory demyelinating polyradiculoneuropathy.
Most commonly caused by
Campylobacter jejuni
Cytomegalovirus infections
PATHOPHYSIOLOGY
CLINICAL FEATURES
Immune complexes accumulate in many tissues and cause inflammation and damage
Affects many organs or the whole body
E.g.
Systemic lupus erythematosus
Rheumatoid arthritis
Rheumatic fever
Ankolysing spondylitis (AS)
Sjogren’s syndrome (SS)
Polyarteritis nodosa
SYSTEMIC AUTOIMMUNE DISEASE Or
NON-SPECIFIC AUTOIMMUNE DISEASE
SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
It is a skin disease due to the production of antinuclear factor (ANF) or antinuclear auto Ab
ANF reacts with the breakdown products of nuclei in the normal wear & tear of cells & form immune complexes which cause the tissue damage.
In these patients, LE cell (a mature neutrophil) appears in blood & bone marrow
Function – Phagocytosis in the presence of ANF.
Malar Rash (SLE)
Appearance of blood red spots over the bridge of nose & cheeks. The lesions take the shape of a butterfly.
Connective tissues of the skin, kidney, heart. Speel & blood vessels are severly damaged resulting in joint pain, fever & anaemia.
Glomerulonephritis due to deposition of immune complex in the glomerulus region.
It is a systemic disease affecting the whole body
CHARACTERISTICS OF SLE
RHEUMATOID ARTHRITIS
It is a chronic systemic disease of the joints
Caused by the auto Antibody of IgM type, called as Rheumatoid factors
CHARACTERISTICS:
The synovial fluid of these patients contain increased no. of T-cells & macrophages.
Marked by inflammatory changes in the synovial membrane & by atrophy of bones.
In later stage, deformity & ankylosis develops.
Figure 43.21
SIGNS
JOINT DEFORMITY IN RHEUMATOID ARTHRITIS
ANKOLYSING SPONDYLITIS
DEFINITON: It is a systemic, rheumatic disorder characterized by
inflammation of the sacroiliac & spinal apophyseal joints.
The exact etiology is unknown.
Most frequent complaint is back pain.
More common in men than in women 7 occurs in the age group 20-40.
CLINICAL FEATURES
PATHOPHYSIOLOGY
SJOGREN’S SYNDROME (SS) The syndrome of dry eyes (keratoconjutivits sicca) in the
absence of rheumatoid arthritis or any of the autoimmune diseases is known as primary Sjogren's syndrome.
keratoconjutivits sicca(dry eyes)
Salivary gland enlargement
Xerostomia(Dryness of
mouth)
PATHOPHYSIOLOGYCLINICAL FEATURES
POLYARTERITIS NODOSADEFINTION: It is a necrotizing angitis involving small and medium arteries The disease ends fatally due to coronary thrombosis, cerebral hemorrhage
or GI bleeding.
PATHOGENESISCLINICAL FEATURES
TRANSITORY DISEASES These are the conditions such as anemia, thrombocytopenia, or
nephritis that occur following certain infections or drug therapy.
Infecting agent Drug
Antigenic alteration in self antigens
Immune response
Tissue damage
MOST COMMON TISSUES AFFECTED Red Blood Cells:
Pernicious Anemia,
Hemolytic anemia
Blood Vessels:
Vasculitis
Endocrine Glands
(Thyroid, Adrenal, Pancreas)
Hashimotto’s Thyroiditis,
Grave’s Disease,
Addison’s Disease,
Diabetes Mellitus
Muscle / Nerve Multiple sclerosis, Myasthenia gravis
Joints: Rheumatoid Arthritis, SLE,
Skin and muscle:Dermatomyositis, Psoriasis, Vitiligo
Organ Disease Crohn's disease, Celiac disease, Ulcerative colitis
GENERALIZED SYMPTOMS Common symptoms
Tissue specific Inflammation and / or destruction Generalize Fatigue, dizziness, weakness Possible low Grade Fever
Specific Symptoms: Vary with the individual disease
Routine investigations asked for diagnosis for Autoimmune diseases:
Complete blood count
Peripheral smear
Synovial fluid analysis
RFT
LFT
Urine analysis
Radiological investigations- X-ray, Ultrasound, MRI, CT scan
Histopathological examination of affected
LABORATORY DIAGNOSIS
Auto-antibodies
Antinuclear antibodies (ANA)
Antineutrophil Cytoplasmic Antibody (ANCA)
Rheumatoid factor
Acute phase proteins
HLA typing
ASO titer
AUTO ANTIBODIES
ANTINUCLEAR ANTIBODIES
Initially discovered in the 1940s using the LE cell test
LE cell test: lacks sensitivity, specificity and predictive value
Nowadays used: Immunofluorescence anti-nuclear antibody test (IF-ANA) and EIA/ELISA
Flow cytometry and nanotechnology
Method of choice: Indirect immunofluorescence (IMF) using cultured Hep2 cells
ACUTE PHASE PROTEINS
Those proteins whose plasma concentration changes by at least 25% during inflammatory states
Occurs in association with infection, trauma, inflammatory arthritis, neoplasms.
Positive reactants/negative reactants
Most widely used – ESR, CRP
CONDITIONS ASSOCIATED WITH INCREASED CRP
Insignificant elevation(<1mg/dL)
Exercise, Flu, Pregnancy, Gingivitis, CVA, Seizures, Angina
Moderate elevation (110mg/dL)
MI, malignancy,
Pancreatitis, Mucosal infection, Most rheumatic diseases
Marked elevation (>10mg/dL)
Acute Bacterial infection, Major trauma, Systemic vasculitis
TREATMENTA) Symptomatic
Anti-inflammatory drugs: SLE, RA
Plasmapheresis: SLE, Guillain-Barre
Splenectomy : ITP
Anticholinesterase and thymectomy: Myasthenia gravis
Hormone replacement: Hashimoto thyroiditis, type I diabetes
B) Immunosuppressive Agents:
Two Categories1. Lympholytic Ionizing
radiation; Antiserums-Antilymphocyte serum, Antithymocyte serum, Anti-RhD
2. Lymphocytotoxic : Antimetabolites, Alkylating agents
BASED ON TYPE OF HYPERSENSITIVITY
REACTION
Type II hypersensitivity reaction (antibodies to cell surface molecules)
Disease Auto-antigen Outcome
Autoimmune hemolytic anaemia
Rh blood group antigens Lysis of RBC by complement and FcR+ cells→ Anaemia
Autoimmune thrombocytopenic purpura
Platelet integrin: GpIIb/IIIa
Abnormal bleeding
Goodpasture’s syndrome
Basement membrane type IV collagen
Glomerulonephritis, pulmonary haemorrhage
Grave’s disease TSH receptor Thyroid overactivity
Hashimoto’s thyroiditis Thyroglobulin, thyroid peroxidase
Thyroid underactivity
Hypoglycemia Insulin receptor (agonist)
Low blood glucose
Disease Autoantigen Outcome
Insulin resistant diabetes
Insulin receptor (antagonist)
High blood glucose, Ketoacidosis
Myasthenia gravis A chain of nicotinic acetylcholine receptor
Progressive weakness
Pemphigus vulgaris Epidermal cadherin Skin blisters
Pernicious anaemia Intrinsic factor, Gastric parietal cell
Anaemia
Rheumatic fever Streptococcal cell wall antigens, antibodies cross react with heart muscles
Arthritis, myocarditis, heart valve scars
Spontaneous infertility Sperm antigens Infertility
Type III: Immune complex disease
Disease Autoantigen Outcome
Ankylosing spondylitis
Immune complexes Damage to vertebra
Mixed essential cryoglobulinemia
Rheumatoid factor, IgG complexes
Arthritis
SLE DNA, histones, ribosomes, smRNP, scRNP
Glomerulonephritis, vasculitis, rash
Type IV: T cell-mediated disease
Disease Auto-antigen Outcome
Multiple sclerosis Myelin oligodendrocyte glycoprotein
Brain invasivion by CD4 cells, weakness
Hashimoto’s thyroiditis
Thyroid antigen Thyroid underactivity
IDDM Pancreatic β-cell antigen
Β-cell destruction
RA Unknown synovial joint antigen
Joint inflammation and destruction
ACKNOWLEDGEMENT
Trust the Laws of Nature First Then Trust Science
The Laws of Nature Never Change The Conclusions of Science are
always changing.
To seek what everybody has sought
Is KnowledgeTo think what nobody has
thoughtIs Innovation
Try your best, everything will be PossibleThank you for ur Patience