74. AUTOIMMUNE DISEASES 74. AUTOIMMUNE DISEASES

Autoimmune diseaseAutoimmune disease

Results from a failure of self-toleranceResults from a failure of self-tolerance Immunological tolerance is specific Immunological tolerance is specific

unresponsiveness to an antigenunresponsiveness to an antigen All individuals are tolerant of their own All individuals are tolerant of their own

(self) antigens(self) antigens

Central and peripheral Central and peripheral tolerancetolerance

Central tolerance is induced by the death Central tolerance is induced by the death of or other changes in immature of or other changes in immature lymphocytes that encounter antigens in lymphocytes that encounter antigens in the generative lymphoid organsthe generative lymphoid organs

Peripheral tolerance results from the Peripheral tolerance results from the recognition of antigens by mature recognition of antigens by mature lymphocytes in peripheral tissueslymphocytes in peripheral tissues

Central tolerance in T Central tolerance in T cellscells

Central tolerance of T cells is the result of high-Central tolerance of T cells is the result of high-affinity recognition of antigens in the thymusaffinity recognition of antigens in the thymus

Some of these self-reactive T cells die Some of these self-reactive T cells die (negative selection), thus eliminating the (negative selection), thus eliminating the potentially most dangerous T cells, which potentially most dangerous T cells, which express high-affinity receptors for self antigens.express high-affinity receptors for self antigens.

Other Tcells of the CD4+ lineage develop into Other Tcells of the CD4+ lineage develop into regulatory T cell that supress self reactivity in regulatory T cell that supress self reactivity in the peripherythe periphery

Peripheral tolerance in T Peripheral tolerance in T cellscells

Peripheral tolerance in T cells is induced by Peripheral tolerance in T cells is induced by multiple mechanismsmultiple mechanisms

Anergy results from the recognition of antigens Anergy results from the recognition of antigens without innate immunity and costimulatorswithout innate immunity and costimulators

The mechanisms of anergy include a block in The mechanisms of anergy include a block in TCR signaling and engagement of inhibitory TCR signaling and engagement of inhibitory receptorsreceptors

Self reactive regulatory T cells supress Self reactive regulatory T cells supress potentially pathogenic T cellpotentially pathogenic T cell

Deletion may occure when T cell encounter self Deletion may occure when T cell encounter self antigensantigens

Central tolerance in B Central tolerance in B cellscells

central tolerance in B lymphocytes central tolerance in B lymphocytes occurs when immature cells recognize occurs when immature cells recognize self antigens in the bone marrow – some self antigens in the bone marrow – some of the cells change their receptors and of the cells change their receptors and others die by apoptosis (negative others die by apoptosis (negative selection) selection)

Peripheral tolerance in B Peripheral tolerance in B cellscells

Is induced when mature B cells Is induced when mature B cells recognize self antigens without T cell recognize self antigens without T cell help - this results in anergy and death of help - this results in anergy and death of the B cellsthe B cells

AutoimmunityAutoimmunity

is defined as an immune respons against self is defined as an immune respons against self antigensantigens

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

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

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

AUTOIMMUNE PATOLOGICAL AUTOIMMUNE PATOLOGICAL RESPONSE- ETIOLOGYRESPONSE- ETIOLOGY

ddisorders areisorders are characterized bycharacterized by chronicity chronicity and usually areand usually are irirreversiblereversible

iincidence: 5%-7% of populationncidence: 5%-7% of population, h, higher frequencies in women, igher frequencies in women, increases with ageincreases with age

factors factors contribute to autoimmunity:contribute to autoimmunity: - internal- internal (HLA association, polymorfism in genes for (HLA association, polymorfism in genes for

cytokines, defect in genes regulating apoptosis, polymorphism cytokines, defect in genes regulating apoptosis, polymorphism in genes for TCR a H immunoglobulin chains, association with in genes for TCR a H immunoglobulin chains, association with immunodeficiencies, hormonal factors) immunodeficiencies, hormonal factors)

- external- external (infection, stress by activation of neuroendocrine‘s (infection, stress by activation of neuroendocrine‘s line and hormonal disbalance, drug and ionization through line and hormonal disbalance, drug and ionization through modification of autoantigens) modification of autoantigens)

Type II hypersensitivity Type II hypersensitivity reaction reaction Ab against cell and tissue antigens may cause tissue injury and Ab against cell and tissue antigens may cause tissue injury and

diseasedisease autoantibodies characterized by a high afinity to antigens, present autoantibodies characterized by a high afinity to antigens, present

in a high level in serum, predominantly in the IgG classin a high level in serum, predominantly in the IgG class autoantibodies against intracelular proteins and nuclear acid, autoantibodies against intracelular proteins and nuclear acid,

cytoplasmatic molecules participating in protein synthesis and cytoplasmatic molecules participating in protein synthesis and expression and regulation of genesexpression and regulation of genes

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

Graves‘ disease, Pernicious anemia, Myastenia gravis, Acute Graves‘ disease, Pernicious anemia, Myastenia gravis, Acute rheumatic fever, Goodpasture‘s syndrome, Pemphigus rheumatic fever, Goodpasture‘s syndrome, Pemphigus vulgaris, Autoimmune hemolytic anemia or trombocytopenic vulgaris, Autoimmune hemolytic anemia or trombocytopenic purpurapurpura

Type III hypersensitivity Type III hypersensitivity reactionreaction

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

Injury is due mainly to leukocyte Injury is due mainly to leukocyte recruitment and inflammation.recruitment and inflammation.

Systemic lupus erythematosus, Systemic lupus erythematosus, Polyarteritis nodosa, Polyarteritis nodosa, Poststreptococcal glomerulonephritisPoststreptococcal glomerulonephritis

Type IV hypersensitivity Type IV hypersensitivity reactionreaction

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

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

CLINICAL CATEGORIESCLINICAL CATEGORIES

systemicsystemic - affect many organs and tissue - affect many organs and tissue

organ localisedorgan localised - affect predominantly one organ - affect predominantly one organ

accompained by affection of other organs accompained by affection of other organs (nonspecific bowel diseases, celiatic disease, (nonspecific bowel diseases, celiatic disease, AI hepatitis, pulmonary fibrosis)AI hepatitis, pulmonary fibrosis)

organ specificorgan specific - affect one organ or group of organs - affect one organ or group of organs

connected withconnected with development or functiondevelopment or function

75. EXAMPLES OF SYSTEMIC 75. EXAMPLES OF SYSTEMIC AUTOIMMUNE DISEASES AUTOIMMUNE DISEASES

examples examples autoantibodies autoantibodies

SYSTEMIC AUTOIMMUNE DISEASESSYSTEMIC AUTOIMMUNE DISEASES

Systemic lupus erythematosusSystemic lupus erythematosus Rheumathoid arthritisRheumathoid arthritis Sjögren‘s syndromeSjögren‘s syndrome DermatopolymyositisDermatopolymyositis Systemic sclerosisSystemic sclerosis Mixed connective tissue disease Mixed connective tissue disease Antiphospholipid syndromeAntiphospholipid syndrome VasculitisVasculitis SarcoidosisSarcoidosis

SYSTEMIC LUPUS ERYTHEMATOSUSSYSTEMIC LUPUS ERYTHEMATOSUS

chronic, inflammatory, multiorgan disorderchronic, inflammatory, multiorgan disorder predominantly affects young women predominantly affects young women

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

general symptoms: general symptoms: include malaise, fever, weight include malaise, fever, weight lossloss

multiple tissuemultiple tissue are involved including the skin, are involved including the skin, mucosa, kidney, joints, brain and cardiovascular mucosa, kidney, joints, brain and cardiovascular systemsystem

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

DIAGNOSTIC TESTSDIAGNOSTIC TESTS

a elevated a elevated ESRESR (erythrocyte sedimentation rate), (erythrocyte sedimentation rate), low low CRPCRP, trombocytopenia, leukopenia, hemolytic anemia, , trombocytopenia, leukopenia, hemolytic anemia, depresed levels of complement (C4, C3), elevated depresed levels of complement (C4, C3), elevated serum gamma globulin levels, immune complexes in serum gamma globulin levels, immune complexes in serumserum

AUTOANTIBODIESAUTOANTIBODIES

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

RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS

cchronic, inflammatory joint disease with systemic involvementhronic, inflammatory joint disease with systemic involvement predominantly affects wpredominantly affects womenomen characterized by an icharacterized by an inflammatory joint lesion in the synovial nflammatory joint lesion in the synovial

membrane, destrmembrane, destruction of the uction of the cartilage and bone, resultcartilage and bone, resultss in in the the joint deformjoint deformationation

clinical features:clinical features: arthritis, fever, fatigue, weakness arthritis, fever, fatigue, weakness, w, weight losseight loss ssystemic featuresystemic features:: vasculitis, pericarditis, uveitis, nodules under vasculitis, pericarditis, uveitis, nodules under

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

Rtg: symmetrical destruction of proximal joints, erosion of carpal bones, distal radioulnar joints

SJÖGREN‘S SYNDROMESJÖGREN‘S SYNDROME

chronic inflammatory disease that affects the exocrine glandschronic inflammatory disease that affects the exocrine glands the primary targetsare the lacrimal and salivary gland duct epitheliumthe primary targetsare the lacrimal and salivary gland duct epithelium general featuresgeneral features: malaise, weakness, fever: malaise, weakness, fever primaryprimary syndrome - features: dry eyes and dry mouth, swollen syndrome - features: dry eyes and dry mouth, swollen

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

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

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

Systemic sclerosisSystemic sclerosis

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

sclerosis)sclerosis) is the most severe form - it has a rapid onset, is the most severe form - it has a rapid onset,

involves more widespread skin hardening, will involves more widespread skin hardening, will generally cause much internal organ damage generally cause much internal organ damage (specifically the lungs and gastrointestinal tract(specifically the lungs and gastrointestinal tract

The The limited formlimited form is much milder is much milder The scleroderma may be limited to the fingers - The scleroderma may be limited to the fingers -

known as known as sclerodactyly.sclerodactyly. The limited form is often referred to as The limited form is often referred to as CREST CREST

syndromesyndrome "CREST" is an acronym for the five main "CREST" is an acronym for the five main features: features: CCalcinosis, alcinosis, RRaynaud's syndrome, aynaud's syndrome, EEsophageal dysmotility, sophageal dysmotility, SSclerodactyy, clerodactyy, TTelangiectasia elangiectasia

Immunological findingsImmunological findings

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

Mixed connective Mixed connective tissue disease tissue disease

combines features of polymyositis, systemic lupus combines features of polymyositis, systemic lupus erythematosus, scleroderma, and erythematosus, scleroderma, and dermatomyositis, and is thus considered an dermatomyositis, and is thus considered an overlap syndromeoverlap syndrome

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

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

and an anti-U1-RNP antibody (ENA)and an anti-U1-RNP antibody (ENA)

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

• a connective-tissue disease related to polymyositis (PM) that is 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

DermatopolymyositisDermatopolymyositis

Elevated creatine phosphokinase (CPK)Elevated creatine phosphokinase (CPK)

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

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

Antiphospholipid Antiphospholipid syndromesyndrome

autoimautoimmmunune disease characterized by vein and e disease characterized by vein and arterial thrombosis, repeated abortionsarterial thrombosis, repeated abortions

accompanied by anti-phospholipid accompanied by anti-phospholipid autoantibodies (autoantibodies (APAAPA) and antibodies against ) and antibodies against ββ2-glykoprotein I2-glykoprotein I

VasculitisVasculitis

characterized by inflammatory destruction characterized by inflammatory destruction of the bloodstream leads into thrombosis and of the bloodstream leads into thrombosis and

aneurysmaaneurysma pproliferaroliferation of the tion of the intimintimal part of blood-vessel al part of blood-vessel

wall and wall and fibrinoid nefibrinoid necrosiscrosis affect mostly lung, kidneys, skinaffect mostly lung, kidneys, skin

diagnostic tests: diagnostic tests: elevated ESR, CRP, elevated ESR, CRP, leukocytosis, biopsy of affected organ- leukocytosis, biopsy of affected organ- necrosis, granulomas, angiographynecrosis, granulomas, angiography

Vasculitis Vasculitis

p- ANCA p- ANCA (myeloperoxidase) positivity ((myeloperoxidase) positivity (Polyarteritis Polyarteritis nodosa, Churg- Strauss,nodosa, Churg- Strauss, Microscopic polyartheritis Microscopic polyartheritis nodosa, Good- nodosa, Good- Pasture‘sPasture‘s syndrome, Kawasaki syndrome, Kawasaki syndrome)syndrome)

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

ClassificationClassification

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

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

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

Complaints Complaints include fatigue, weakness, fever, include fatigue, weakness, fever, arthralgias, abdominal pain, hypertension, renal arthralgias, abdominal pain, hypertension, renal insufficiency, and neurologic dysfunctioninsufficiency, and neurologic dysfunction

Biopsy showing vasculitis with mononuclear cell infiltrate, usually with multinucleated giant cells

Angiography of a.temporalis• Temporal artery tenderness or decreased pulsation

•Giant cell (temporal) arteritis

SarcoidosisSarcoidosis

multisystem disorder characterized by non-multisystem disorder characterized by non-caseating granulomascaseating granulomas

granulomas most often appear in the lungs or granulomas most often appear in the lungs or the lymph nodesthe lymph nodes

cause of sarcoidosis is not knowncause of sarcoidosis is not known fatigue, weight loss, arthralgia, shortness of fatigue, weight loss, arthralgia, shortness of

breath, a dry cough, skin lesions, bilateral breath, a dry cough, skin lesions, bilateral hilar lymphadenopathyhilar lymphadenopathy

Hypercalcemia, high level of ACE Hypercalcemia, high level of ACE (angiotensin converting enzyme)(angiotensin converting enzyme)

76. EXAMPLES OF ORGAN- 76. EXAMPLES OF ORGAN- SPECIFIC AUTOIMMUNE SPECIFIC AUTOIMMUNE DISEASESDISEASES

diseasesdiseases autoantibodiesautoantibodies

ORGANOLEPTIC AUTOIMMUNE ORGANOLEPTIC AUTOIMMUNE DISEASESDISEASES

Ulcerative colitisUlcerative colitis Crohn‘s diseaseCrohn‘s disease Coeliac diseaseCoeliac disease Autoimmune hepatitisAutoimmune hepatitis Primary biliary cirhosisPrimary biliary cirhosis Primary sclerotic cholangoitisPrimary sclerotic cholangoitis Pulmonary fibrosisPulmonary fibrosis

Ulcerative colitisUlcerative colitis

chronic inflammation of the large intestine chronic inflammation of the large intestine mucose and submucose mucose and submucose

features: diarrhea mixed with blood and mucusfeatures: diarrhea mixed with blood and mucus extraintestinal features (artritis, uveitis)extraintestinal features (artritis, uveitis) autoantibodies autoantibodies against against pANCApANCA, a- large , a- large

intestine intestine

Crohn‘s diseaseCrohn‘s disease

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

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

antibodies againstantibodies against Saccharomyces Saccharomyces cerevisiaecerevisiae ( (ASCAASCA), a- pancreas), a- pancreas

Coeliac diseaseCoeliac disease

a malabsorption syndrome characterized by marked a malabsorption syndrome characterized by marked atrophy and loss of function of the villi of the jejunum atrophy and loss of function of the villi of the jejunum

inflammatory bowell disease arise from gliadin inflammatory bowell disease arise from gliadin exposition exposition

autoantibodies againstautoantibodies against endomysium, the most endomysium, the most specific = specific = tissue transglutaminazetissue transglutaminaze; antibodies ; antibodies against gliadin are nonspecific against gliadin are nonspecific

biopsy of the jejunum with findings of the villi atrophybiopsy of the jejunum with findings of the villi atrophy

Primary biliary cirhosisPrimary biliary cirhosis autoimmune disease of the liver marked by the slow autoimmune disease of the liver marked by the slow

progressive destruction of the small bile ducts; can lead to progressive destruction of the small bile ducts; can lead to cirrhosiscirrhosis

AMAAMA= antimitochondrial autoantibodies= antimitochondrial autoantibodies

Primary sclerotic cholangoitis Primary sclerotic cholangoitis aa chronic disorder of the liver in which the chronic disorder of the liver in which the bile bile ducts become ducts become

inflamed, thickened, scarred (sclerotic), and obstructedinflamed, thickened, scarred (sclerotic), and obstructed process can in time destroy the bile ducts and lead to process can in time destroy the bile ducts and lead to

cirrhosis cirrhosis pANCApANCA

AUTOIMMUNE HEPATITISAUTOIMMUNE HEPATITIS

typetype II – association with autoantibodies against – association with autoantibodies against smooth muscles smooth muscles SMASMA, ANA, ANCA, SLA, ANA, ANCA, SLA

type II –type II – autoantibodies against microsomes autoantibodies against microsomes LKM-1 LKM-1 = liver-kidney microsomes= liver-kidney microsomes

type IIItype III – autoantibodies against – autoantibodies against SLA SLA (solubile liver (solubile liver

antigen)antigen)

type IVtype IV – overlap syndrome with PBC – – overlap syndrome with PBC – autoantibodies against mitochondries autoantibodies against mitochondries AMAAMA

Pulmonary fibrosisPulmonary fibrosis

isis associated with SLE, RA, systemic associated with SLE, RA, systemic sclerosis, polymyositissclerosis, polymyositis

autoantibodies nonspecific- RF, ANA, others autoantibodies nonspecific- RF, ANA, others autoantibodies in according with associate autoantibodies in according with associate disease disease

biopsy, spirometry, X-raybiopsy, spirometry, X-ray

ORGAN SPECIFIC AUTOIMMUNE ORGAN SPECIFIC AUTOIMMUNE DISEASESDISEASES

Autoimmune endocrinopathyAutoimmune endocrinopathy Autoimmune neurological diseasesAutoimmune neurological diseases Autoimmune cytopeniaAutoimmune cytopenia Autoimmune cutaneous diseasesAutoimmune cutaneous diseases Autoimmune eye diseasesAutoimmune eye diseases

AUTOIMMUNE ENDOCRINOPATHYAUTOIMMUNE ENDOCRINOPATHY

Hashimoto‘s thyroiditisHashimoto‘s thyroiditis Graves-Basedow diseaseGraves-Basedow disease Postpartum thyroiditisPostpartum thyroiditis Diabetes mellitus I. typeDiabetes mellitus I. type Addison‘s diseaseAddison‘s disease Autoimmune polyglandular syndromeAutoimmune polyglandular syndrome Pernicious anemiaPernicious anemia

Hashimoto‘s thyroiditisHashimoto‘s thyroiditis

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

autoantibodies against thyroidal peroxidase (autoantibodies against thyroidal peroxidase (a-a-

TPOTPO) and/or against thyroglobulinu () and/or against thyroglobulinu (a-TGa-TG))

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

Grave‘s diseaseGrave‘s disease

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

exophtalmos)exophtalmos)

autoantibodies against autoantibodies against thyrotropinthyrotropin receptor,receptor, autoantibodies cause thyroid cells proliferation autoantibodies cause thyroid cells proliferation

Diabetes mellitus (insulin- Diabetes mellitus (insulin- dependent) dependent)

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

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

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

islets are islets are infiltrated with B and T cellsinfiltrated with B and T cells

Addison‘s diseaseAddison‘s disease

a disorder involving disrupted functioning of the a disorder involving disrupted functioning of the adrenal cortex, this resullt in decreased adrenal cortex, this resullt in decreased production of cortisol and aldosterone production of cortisol and aldosterone

features malaise, pain of muscle and joint, features malaise, pain of muscle and joint, hyperpigmentationhyperpigmentation

autoantibodies against adrenal cortex and/or autoantibodies against adrenal cortex and/or 21-hydroxylase, 21-hydroxylase, autoantibodies against autoantibodies against 17-17-hydroxylasehydroxylase

Polyglandular autoimmune syndromePolyglandular autoimmune syndrome

combination of several different AI combination of several different AI endocrinopathiesendocrinopathies

autoantibodies appear in according with the autoantibodies appear in according with the

connected disorders connected disorders

Pernicious anemiaPernicious anemia the deficiency of the intrinsic factor results in the deficiency of the intrinsic factor results in

inadequate and abnormal formation of inadequate and abnormal formation of erythrocytes and failure to absorb vitamin B12 erythrocytes and failure to absorb vitamin B12

clinical feature- atrophic gastritis, macrocytic clinical feature- atrophic gastritis, macrocytic anemiaanemia

autoantibodies against autoantibodies against parietal cells of gastric parietal cells of gastric mucosemucose, against intristic factor (transport vit. , against intristic factor (transport vit. B12)B12)

AUTOIMMUNE NEUROPATHYAUTOIMMUNE NEUROPATHY

Guillain-Barré syndrome (acute idiopathic Guillain-Barré syndrome (acute idiopathic polyneuritis)polyneuritis)

Myasthenia gravisMyasthenia gravis

Multiple sclerosisMultiple sclerosis

Guillain-Barre syndromeGuillain-Barre syndrome

inflammatory demyelinate peripheral neuropathy that inflammatory demyelinate peripheral neuropathy that causes progressive muscle weakness and paralysiscauses progressive muscle weakness and paralysis

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

jej.) jej.)

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

immunologic findings: autoantibodies against immunologic findings: autoantibodies against ganglioside ganglioside membrane (cross-react with membrane (cross-react with Campylobacter jejuni lipopolysacharids) Campylobacter jejuni lipopolysacharids)

Myasthenia gravisMyasthenia gravis

chronic disease resulting from faulty chronic disease resulting from faulty neuromuscular transmissionneuromuscular transmission

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

dysfunction result from blockage and depletion dysfunction result from blockage and depletion of acetylcholin receptors at the myoneural of acetylcholin receptors at the myoneural junctionjunction

immunological findings: autoantibodies against immunological findings: autoantibodies against Ach receptorsAch receptors

ptosis of the eyeptosis of the eye

Multiple sclerosisMultiple sclerosis

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

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

autoantibodies against MOGautoantibodies against MOG (myelin-oligodendrocyte (myelin-oligodendrocyte glycoprotein) glycoprotein)

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

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

AUTOIMMUNE DISORDERS OF AUTOIMMUNE DISORDERS OF REPRODUCTIVE ORGANSREPRODUCTIVE ORGANS

Autoimmune men‘s infertility = autoimmune Autoimmune men‘s infertility = autoimmune orchitisorchitis

- autoantibodies against - autoantibodies against sperms sperms

Premature Ovarian FailurePremature Ovarian Failure = lymphocytic oophoritis= lymphocytic oophoritis - autoantibodies against enzymes participate in - autoantibodies against enzymes participate in steroidogenesissteroidogenesis

- autoantibodies against- autoantibodies against 17-hydroxylase 17-hydroxylase, ,

AUTOIMMUNE CYTOPENIAAUTOIMMUNE CYTOPENIA

AI hemolytic diseaseAI hemolytic disease- autoantibodies - autoantibodies against membrane erythrocyte antigens against membrane erythrocyte antigens

AI trombocytopeniaAI trombocytopenia - autoantibodies against - autoantibodies against

trombocyte antigens (GPIIb/IIIa) trombocyte antigens (GPIIb/IIIa)

AI neutropeniaAI neutropenia - autoantibodies against - autoantibodies against membrane neutrofil antigensmembrane neutrofil antigens

EYE DISEASEEYE DISEASE

UveitisUveitis - the autoreactive T cells react with retinal S - the autoreactive T cells react with retinal S autoantigen autoantigen

Bullous pemphigoidBullous pemphigoid

an autoimmune bullous disease of the skin an autoimmune bullous disease of the skin and mucosaand mucosa

the blisters form beneath the epidermis at the the blisters form beneath the epidermis at the dermal- epidermal junction dermal- epidermal junction

lesions demonstrate deposition of antibody lesions demonstrate deposition of antibody and complement along skin basement and complement along skin basement membranemembrane

circulating antibasement membrane circulating antibasement membrane antibodies also can be detectedantibodies also can be detected

Pemphigus vulgarisPemphigus vulgaris

an erosive disease of the skin and mucous an erosive disease of the skin and mucous membranes characterized by intraepidermal membranes characterized by intraepidermal blisters blisters

skin lesions show antibody (mainly IgG) skin lesions show antibody (mainly IgG) deposition and complement components in deposition and complement components in squamous intercellular spaces (when squamous intercellular spaces (when examined by imunofluorescence)examined by imunofluorescence)

Dermatitis herpetiformis (Duhring)Dermatitis herpetiformis (Duhring)

autoimmune disease affect skin, associate with autoimmune disease affect skin, associate with coeliac disease coeliac disease

autoantibodies against endomysium, more autoantibodies against endomysium, more specific specific against tissue transglutaminaze against tissue transglutaminaze

biopsy of skin: IgA deposition on the dermal biopsy of skin: IgA deposition on the dermal papilles papilles

biopsy of jejunum/duodenum:biopsy of jejunum/duodenum: atrophy of the intestineatrophy of the intestine villi villi

Psoriasis Psoriasis

Disorder which affects the skin and joints, Disorder which affects the skin and joints, commonly causes red scaly patches to appear commonly causes red scaly patches to appear on the skinon the skin

T cells become active, migrate to the dermis T cells become active, migrate to the dermis and trigger the release of cytokines which and trigger the release of cytokines which cause inflammation and the rapid production of cause inflammation and the rapid production of skin cellsskin cells

It is not known what initiates the activation of It is not known what initiates the activation of the T cellsthe T cells

77. IMMUNOSUPRESSION77. IMMUNOSUPRESSION

non-specific treatmentnon-specific treatmentexamples of drugsexamples of drugsindicationindicationrisksrisks

ImmunosuppressantsImmunosuppressants

are drugs that inhibit or prevent activity of the immune are drugs that inhibit or prevent activity of the immune systemsystem

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

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

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

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

GlucocorticoidsGlucocorticoids

suppress the cell-mediated immunity- act by suppress the cell-mediated immunity- act by inhibiting genes that code for the cytokines IL-inhibiting genes that code for the cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, and TNF-γ, 1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, and TNF-γ, the most important of which is the IL-2the most important of which is the IL-2

Smaller cytokine production reduces the T cell Smaller cytokine production reduces the T cell proliferation.proliferation.

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

GlucocorticoidsGlucocorticoids leads to diminished eicosanoid production, leads to diminished eicosanoid production,

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

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

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

Drugs affecting the Drugs affecting the proliferation of both T cells and proliferation of both T cells and B cellsB cells

CyclophosphamideCyclophosphamide -very efficient in the therapy -very efficient in the therapy of of systemic lupus erythematosus, autoimmune systemic lupus erythematosus, autoimmune hemolytic anemias, Wegener's granulomatosishemolytic anemias, Wegener's granulomatosis

high doses cause pancytopenia and hemorrhagic high doses cause pancytopenia and hemorrhagic cystitiscystitis

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

Drugs affecting the Drugs affecting the proliferation of both T cells and proliferation of both T cells and B cellsB cells

AzathioprineAzathioprine is a purine synthesis inhibitor, is a purine synthesis inhibitor, inhibiting the proliferation of cells, especially inhibiting the proliferation of cells, especially leukocytes; SLE, RA, sclerosis multiplex, leukocytes; SLE, RA, sclerosis multiplex, transplantationtransplantation

Mycophenolate mofetilMycophenolate mofetil – affects the enzyme – affects the enzyme that controls the purine synthesisthat controls the purine synthesis

Used in transplantation of solid organUsed in transplantation of solid organ

Drugs blocking the Drugs blocking the activation of lymphocytesactivation of lymphocytes TacrolimusTacrolimus - prevents the cell from transitioning from the G - prevents the cell from transitioning from the G00

into Ginto G11 phase of the cell cycle phase of the cell cycle Used to prevent rejection reactions, atopic eczemaUsed to prevent rejection reactions, atopic eczema

SirolimusSirolimus - affects the signal transduction of T cells and their - affects the signal transduction of T cells and their clonal proliferationclonal proliferation

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

Used to prevent rejection reactionsUsed to prevent rejection reactions

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

Monoclonal antibodiesMonoclonal antibodies

Monoclonal antibodies are directed towards Monoclonal antibodies are directed towards exactly defined antigensexactly defined antigens

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

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

Immunosuppression- Immunosuppression- kidney transplantationkidney transplantation

Prevent the acute kidney rejection, tend to Prevent the acute kidney rejection, tend to eliminate side effectseliminate side effects

Induction by daclizumab Induction by daclizumab

Therapy: Glucocorticoids + mycophenolate mofetil Therapy: Glucocorticoids + mycophenolate mofetil + tacrolimus (or cyclosporin A) + tacrolimus (or cyclosporin A)