AUTOIMMUNE DISEASES

Martina Vachová

Department of Immunology and Allergology Faculty of Medicine and Faculty Hospital in Pilsen

AUTOIMMUNE DISEASES

chronic and usually irreversible incidence: 5%-7% of population, higher frequencies in women, increases with age

Autoimmune diseases

Result from a failure of self-tolerance Immunological tolerance is specific unresponsiveness

to an antigen All individuals are tolerant of their own (self) antigens

Autoimmunity

is defined as an immune response against self antigens

The principal factors in the development of autoimmunity are the inheritance of susceptibility genes and environmental triggers, such as infections

Most autoimmune diseases are polygenic and are asssociated with multiple gene loci, the most important of which are the MHC genes

Infections may activate self-reactive lymphocytes, thereby triggering the development of autoimmune diseases

AUTOIMMUNE PATOLOGICAL RESPONSE- ETIOLOGY

Factors contributing to autoimmunity: - internal (HLA association, polymorphism of cytokine

genes, defect in genes regulating apoptosis, polymorphism in genes for TCR and H immunoglobulin chains, association with immunodeficiency, hormonal factors)

- external (infection, stress by activation of neuroendocrinal axis and hormonal dysbalance, drug and ionization through modification of autoantigens)

Mechanism of tissue damage:- Type II, III and IV reaction of hypersensitivity

Type II hypersensitivity reaction

IgM and IgG Ab promote the phagocytosis of cells which they bind, induce inflammation by complement – and Fc receptor- mediated leukocyte recruitment , and may interfere with the functions of cells by binding to essential molecules and receptors.

Graves‘ disease, Pernicious anemia, Myasthenia gravis, Acute rheumatic fever, Goodpasture‘s syndrome, Pemphigus vulgaris, Autoimmune hemolytic anemia or thrombocytopenic purpura

Type III hypersensitivity reaction

Ab may bind to circulating antigens to form immune complexes, which deposit in vessels and cause tissue injury

Injury is mainly due to leukocyte recruitment and inflammation

Systemic lupus erythematosus, Polyarteritis nodosa, Poststreptococcal glomerulonephritis

Type IV hypersensitivity reaction

T cell- mediated diseases are caused by Th1-mediated delayed-type hypersensitivity reactions or Th17- mediated inflammatory reactions, or by killing of host cells by CD8+ CTLs (cytotoxic lymphocytes).

Diabetes mellitus (insulin-dependent), Rheumatoid arthritis, Multiple sclerosis, Inflammatory bowel disease

Autoimmune diseases

Systemic Organ-specific

Organ-localised

CLINICAL CATEGORIES systemic - affect many organs and tissues - organ non-specific autoantibodies

organ specific - affect one organ - organ specific autoantibodies or autoreactive T

lymphocytes

organ localised - affect predominantly one organ accompanied by

affection of other organs (inflammatory bowel diseases, coeliac disease, AI hepatitis, pulmonary fibrosis)

- organ non-specific autoantibodies

EXAMPLES OF SYSTEMIC AUTOIMMUNE DISEASES

examples autoantibodies

SYSTEMIC AUTOIMMUNE DISEASES

Systemic lupus erythematosus Rheumathoid arthritis Sjögren‘s syndrome Dermatopolymyositis Systemic sclerosis Mixed connective tissue disease Vasculitis

SYSTEMIC LUPUS ERYTHEMATOSUS

chronic, inflammatory, multiorgan disorder

autoantibodies react with nuclear material and attack cell function, immune complexes with dsDNA deposit in the tissues

general symptoms: include malaise, fever, weight loss

multiple tissues are involved including the skin, mucosa, kidney, joints, brain and cardiovascular system

characteristic features: butterfly rash, renal involvement, CNS manifestation, pulmonary fibrosis

DIAGNOSTIC TESTS

an elevated ESR (erythrocyte sedimentation rate), low CRP, trombocytopenia, leucopenia, hemolytic anemia, decreased levels of complement compounds (C4, C3), elevated serum Ig levels, immune complexes in serum

AUTOANTIBODIES

Autoantibodies: ANA, dsDNA (double-stranded), ENA (SS-A/Ro, SS-B/La, Sm), against histones, phospholipids

RHEUMATOID ARTHRITIS

chronic, inflammatory disease with systemic involvement characterized by an inflammatory joint lesion in the synovial

membrane, destruction of the cartilage and bone, results in the joint deformation

clinical features: arthritis, fever, fatigue, weakness, weight loss systemic features: vasculitis, pericarditis, uveitis, nodules under skin,

intersticial pulmonary fibrosis diagnostic tests: elevated C- reactive protein and ESR, elevated serum gammaglobulin levels - autoantibodies against IgG = rheumatoid factor (RF), a-CCP (cyclic citrulline peptid), ANA - X-rays of hands and legs- show a periarticular porosis, marginal erosion

SJÖGREN‘S SYNDROME

chronic inflammatory disease affecting exocrine glands the primary targets are the lacrimal and salivary gland duct

epithelium general features: malaise, weakness, fever primary syndrome - features: dry eyes and dry mouth, swollen

salivary glands, dryness of the nose, larynx, bronchi and vaginal mucosa, involvement kidney, central and periferal nervous system, arthritis

secondary syndrome – is associated with other AI diseases (SLE, RA, sclerodermia, polymyositis, primary biliary cirhosis,AI thyroiditis)

autoantibodies against ENA (SS-A, SS-B), ANA, RF The Schirmer test - measures the production of tears

Heliotrope rash is a violaceous eruption on the upper eyelids, often with swelling

• a connective-tissue disease characterized by inflammation

of the muscles and the skin.

Gottron's sign is an erythematous, scaly eruption occurring in symmetric fashion over the MCP and interphalangeal joints

Dermatopolymyositis

Dermatopolymyositis

elevated creatine phosphokinase (CPK)

muscle biopsy (a mixed B- and T-cell perivascular inflammatory infiltrate, perifascicular muscle fiber atrophy)

EMG (electromyogram) autoantibodies - ENA (Jo-1)

Systemic sclerosis

sclerosis in the skin or other organs Diffuse scleroderma (progressive systemic

sclerosis) is the most severe form, involves skin, will generally cause internal organ

damage (specifically the lungs and gastrointestinal tract)

The limited form is much milder The limited form is often referred to as CREST

syndrome (CREST is an acronym for the five main features: Calcinosis, Raynaud's syndrome, Esophageal dysmotility, Sclerodactyly, Telangiectasia

Immunological findings

ANA, ENA - anti-Scl-70 (fluorescence of nucleolus), anti-centromers

Mixed connective tissue disease

combines features of polymyositis, systemic lupus erythematosus, scleroderma, and dermatomyositis (overlap syndrome)

features : joint pain/swelling, malaise, Raynaud phenomenon, muscle inflammation and sclerodactyly (thickening of the skin of the pads of the fingers)

distinguishing laboratory characteristics: a positive, speckled anti-nuclear antibody (ANA) and

anti-U1-RNP antibody (ENA)

Vasculitis

characterized by inflammatory destruction of vessels leading to thrombosis and

aneurysms

affect mostly lung, kidneys, skin

diagnostic tests: elevated ESR, CRP, leucocytosis, biopsy of affected organ (necrosis, granulomas), angiography

Vasculitis

p- ANCA (myeloperoxidase) positivity (Polyarteritis nodosa, Churg- Strauss, Microscopic polyarteritis nodosa)

c- ANCA (serin proteinase) positivity (Wegener granulomatosis, Churg- Strauss syndrome)

Classification

Large vessel vasculitis (Takayasu arteritis, Giant cell (temporal) arteritis)

Medium vessel vasculitis (Polyarteritis nodosa, Wegener's granulomatosis, Kawasaki disease)

Small vessel vasculitis (Churg-Strauss arteritis, Microscopic polyarteritis, Henoch-Schönlein purpura)

Symptoms: fatigue, weakness, fever, arthralgias, abdominal pain, hypertension, renal insufficiency, and neurologic dysfunction

EXAMPLES OF ORGAN LOCALISED AUTOIMMUNE DISEASES

diseases autoantibodies

ORGAN LOCALIZED AUTOIMMUNE DISEASES

Ulcerative colitis Crohn‘s disease Autoimmune hepatitis Primary biliary cirhosis Pulmonary fibrosis

Ulcerative colitis

chronic inflammation of the large intestine mucosa and submucosa

features: diarrhea, bloody and mucus stools extraintestinal features (arthritis, uveitis) autoantibodies against pANCA, a- large intestine

Crohn‘s disease

the granulomatous inflammation of whole intestinal wall with ulceration and scarring that can result in abscess and fistula formation

the inflammation in Crohn's disease the most commonly affects the terminal ileum, presents with diarrhea and is accompanied by extraintestinal features - iridocyclitis, uveitis, artritis, spondylitis

antibodies against Saccharomyces cerevisiae

(ASCA), a- pancreas

Primary biliary cirhosis

autoimmune disease of the liver marked by the slow progressive destruction of the small bile ducts; can lead to cirrhosis

AMA= antimitochondrial autoantibodies

AUTOIMMUNE HEPATITIS

type I – association with autoantibodies against smooth muscles SMA, ANA, ANCA, SLA

type II – autoantibodies against microsomes LKM-1

= liver-kidney microsomes

type III – autoantibodies against SLA (solubile liver

antigen)

ORGAN SPECIFIC AUTOIMMUNE DISEASES

Autoimmune endocrinopathy Autoimmune neurological diseases Autoimmune cytopenia

AUTOIMMUNE ENDOCRINOPATHY

Hashimoto‘s thyroiditis Graves-Basedow disease Diabetes mellitus I. type Addison‘s disease Autoimmune polyglandular syndrome Pernicious anemia

Hashimoto‘s thyroiditis

thyroid disease result to hypothyroidism on the base of lymphocytes and plasma cells infiltrate

autoantibodies against thyroidal peroxidase (a-

TPO) and/or against thyroglobulin (a-TG)

infiltrate of plasma cells and lymphocytes with germinal center formation is seen in this thyroid

Grave‘s disease

thyrotoxicosis from overproduction of thyroid hormone (patient exhibit fatigue, nervousness, increased sweating, palpitations, weight loss,

exophtalmus)

autoantibodies against thyrotropin receptor, autoantibodies cause thyroid cells proliferation

Diabetes mellitus (insulin- dependent)

characterized by an inability to process sugars in the diet, due to a decrease in or total absence of insulin production

results from immunologic destruction of the insuline- producing β-cells of the islets of Langerhans in the pancreas

autoantibodies against GAD- glutamic acid decarboxylase = primary antigen), autoantibodies anti- islet cell, anti- insulin

islets are infiltrated with B and T cells

Polyglandular autoimmune syndrome

combination of several different AI endocrinopathies

autoantibodies appear in according with the

connected disorders

Pernicious anemia

the deficiency of the intrinsic factor results in inadequate and abnormal formation of erythrocytes and failure to absorb vitamin B12

clinical feature- atrophic gastritis, macrocytic anemia autoantibodies against parietal cells of gastric

mucose, against intrinsic factor (transportation of B12 vitamin)

AUTOIMMUNE NEUROPATHY

Guillain-Barré syndrome (acute idiopathic polyneuritis)

Myasthenia gravis

Multiple sclerosis

Guillain-Barré syndrome

inflammation demyelinates peripheral nerves that causes progressive muscle weakness and paralysis

the cause is the loss of myelin occurs often 1-3 weeks after infection

(Campylobacter jej.)

features: progressive weakness and paresthesia of the lower and later upper extremitas and respiratory muscles, weakness can leads to paralysis and respiratory failure

immunologic findings: autoantibodies against ganglioside membrane

Myasthenia gravis

chronic disease with impaired neuromuscular transmission

characterized by muscle weakness and fatigue the muscle weakness and neuromuscular dysfunction

result from blockage and depletion of acetylcholine receptors at the myoneural junction

immunological findings: autoantibodies against Ach receptors

ptosis of the eye

Multiple sclerosis

chronic demyelinizing disease with abnormal reaction T cells to myeline protein on the base of mimicry between a virus and myeline protein

features: weakness, ataxia, impaired vision, urinary bladder dysfunction, paresthesias, mental abberations

autoantibodies against MOG (myelin-oligodendrocyte glycoprotein)

Magnetic resonance imaging of the brain and spine shows areas of demyelination

The cerebrospinal fluid is tested for oligoclonal bands, can provide evidence of chronic inflammation of the central nervous system

AUTOIMMUNE CYTOPENIA

AI hemolytic disease- autoantibodies against membrane erythrocyte antigens

AI trombocytopenia - autoantibodies against

trombocyte antigens (GPIIb/IIIa)

AI neutropenia - autoantibodies against membrane neutrofil antigens

IMMUNOSUPPRESSION

non-specific treatmentexamples of drugsindicationrisks

Immunosuppressants

Drugs that inhibit or prevent activity of the immune system

They are used in immunosuppressive therapy to: Prevent the rejection of transplanted organs and

tissues (bone marrow, heart, kidney, liver) Treat autoimmune diseases or diseases that are

most likely of autoimmune origin (rheumatoid arthritis, multiple sclerosis, myasthenia gravis, systemic lupus erythematosus, Crohn's disease, pemphigus, ulcerative colitis).

Treat some other non-autoimmune inflammatory diseases (allergic asthma, atopic eczema).

Glucocorticoids

suppress the cell-mediated immunity- act by inhibiting genes that code for various cytokines (e.g.IL-2)

decrease cytokine production reduces the T cell proliferation.

suppress the humoral immunity, causing B cells to express smaller amounts of IL-2 and IL-2 receptors- this diminishes both B cell clone expansion and antibody synthesis.

Glucocorticoids leads to diminished eicosanoid production,

suppression of the cyclooxygenase expression Glucocorticoids also stimulate the lipocortin-1

escaping to the extracellular space, where it binds to the leucocyte membrane receptors and inhibits : epithelial adhesion, migration, chemotaxis, phagocytosis, respiratory burst, and the release of various inflammatory mediators from neutrophils, macrophages, and mastocytes.

side-effects: hypertension, dyslipidemia, hyperglycemia, peptic ulcers, osteoporosis, disturbed growth in children

Drugs affecting the proliferation of both T cells and B cells

Cyclophosphamide -very efficient in the therapy of systemic lupus erythematosus, autoimmune hemolytic anemias

high doses cause pancytopenia and hemorrhagic cystitis

Methotrexate is a folic acid antagonist, acts during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of the cell cycle; used in the treatment of autoimmune diseases (RA, Crohn's disease) and in transplantations.

Drugs affecting the proliferation of both T cells and B cells

Azathioprine is a purine synthesis inhibitor, inhibiting the proliferation of cells, especially leucocytes; SLE, RA, sclerosis multiplex, transplantation

Mycophenolate mofetil – affects the enzyme that controls the purine synthesis

Used in transplantation of solid organ

Drugs blocking the activation of lymphocytes Tacrolimus - prevents the cell from transitioning from

the G0 into G1 phase of the cell cycle Used to prevent rejection reactions, atopic eczema

Cyclosporin A- inhibits calcineurin, which is responsible for activating the transcription of interleukin-2; inhibits cytokines production and interleukin release

Used to prevent rejection reactions

Side effects: nephrotoxicity, neurotoxicity, hypertension, dyslipidemia, hyperglycemia

Monoclonal antibodies

Monoclonal antibodies are directed towards exactly defined antigens

Daclizumab - acts by binding the IL-2a receptor's α chain, preventing the IL-2 induced clonal expansion of activated lymphocytes and shortening their survival

used in the prophylaxis of the acute organ rejection after the bilateral kidney transplantation

Thank you for your attention!