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

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