Autoimmune diseases

Autoimmunity (AI) refers to the body's immune response to its own components - autoantigens. A potential autoantigen is any protein, a variety of carbohydrates and lipids. The immune response to such an antigen is both humoral and cell-mediated, the presence of autoantibodies and autoreactive T-lymphocytes, can be demonstrated, which damage the body's tissues, thus developing autoimmune diseases. They mainly affect young women.


 * Division of autoimmune diseases
 * 1) Localized (organ-specific) - the immune response is directed against a specific tissue or organ.
 * 2) Systemic (non-organ-specific) - affects more organs.


 * Physiological mechanisms of autotolerance
 * 1) Clonal deletions - during the maturation of immunocompetent T- and B-lymphocytes, those that would react with the body's own antigens are eliminated.
 * 2) Clonal anergy - loss or reduction of reactivity of immunocompetent cells specific against their own antigens.
 * 3) Peripheral inhibition - suppression of a reactive immunocompetent cell by other regulatory cells of the immune system (especially TS - CD-8+ suppressors).
 * 4) Immunological privilege - e.g. cornea, testicular canals, myelin sheaths - creates a barrier that prevents the passage of T-lymphocytes or cells of these tissues express Fas-ligand on their surface, which binds to the Fas-receptor of activated T-lymphocyte and induces its apoptosis.
 * 1) Immunological privilege - e.g. cornea, testicular canals, myelin sheaths - creates a barrier that prevents the passage of T-lymphocytes or cells of these tissues express Fas-ligand on their surface, which binds to the Fas-receptor of activated T-lymphocyte and induces its apoptosis.


 * Mechanisms disrupting self-tolerance
 * 1) Alteration of self-antigen by binding of another molecule.
 * 2) Cross-reactivity of the antibody against two antigens, one of which is intrinsic and the other foreign.
 * 3) Polyclonal activation of B-lymphocytes.
 * 4) Imbalance between TH and TS.
 * 5) Disclosure of sequestered self-antigen against which immunotolerance has not developed.
 * 6) Genetic predisposition (association with HLA).
 * 1) Genetic predisposition (association with HLA).

T-lymphocytes

 * increased expression of costimulatory molecules in the tissue: transgenic expression - B7, IL-2, naturally e.g. infection,
 * disorders of expression of inactivating costimulatory pathway molecules on lymphocytes: CTLA-4,
 * mutations leading to apoptotic signal disorder: Fas (lpr / lpr), Fas-L (gld / gld), IL-2-/-, IL-2Rα-/-, IL-2Rβ-/-,
 * T cell-mediated suppression disorder: transfer of T cell subpopulations,
 * polyclonal stimulation: superantigen.

B-lymphocytes

 * polyclonal stimulation: LPS.
 * A - Genetic factors
 * 1) MHC genes:
 * 2) *	MHC II: Type I DM.
 * 3) ** HLA DR4 (5×–6× > risk).
 * 4) ** HLA DR3/DR4 (25× > risk).
 * 5) *	MHC I: Ankylosing spondylarthritis HLA-B27 (90×–100× > risk)
 * 6) Other genes:
 * 7) * IL-2 gene polymorphism (DM type 1),
 * 8) * gene near CTLA-4 (DM type 1),
 * 9) * C2 and C4 genetic deficiency (SLE),
 * 10) *	Fas a FasL (ALPS).


 * B - The role of infection in the autoimmune process
 * Viral and bacterial infections can theoretically affect the onset and exacerbation of autoimmune disease.
 * Infectious microorganisms are not present in the autoimmune lesion, that means the cause of autoimmune damage is not the infection, but the result of an immune response that can be induced or dysregulated by the presence of the microorganism.
 * Potential mechanisms of influencing the autoimmunity of infections,
 * costimulator expression (B7, IL-2, IFN-γ,…),
 * alterations of own antigens, which may thus become partially cross-reactive,
 * access to "sequestered" antigen (intraocular proteins, spermatozoa),
 * molecular mimicry = cross-reactivity against foreign and self antigen.


 * C - Other factors in the development of AI disease
 * Anatomical tissue damage (inflammation, trauma, ischemia = access to "sequestered" antigen).
 * Hormonal effects.
 * Higher incidence in women than in men (SLE ~ 10F/1M; SLE model (NZW/NZB) F1 only in females and affected by androgen therapy).

Localized autoimmune diseases

 * 1) Autoimmune hemolytic anemia (against erythrocytes), thrombocytopenia (against platelets), agranulocytosis (against granulocytes).
 * 2) Diabetes mellitus type I (against B-cells of Langerhans islets).
 * 3) Chronic gastritis type A (against parietal cells of the gastric mucosa and intrinsic factor).
 * 4) Goodpasture's syndrome (against basement membranes, especially in the kidneys and lungs).
 * 5) Hashimoto's thyroiditis (against colloid and thyrocytes).
 * 6) Graves-Basedow goiter (against TSH-thyrocyte receptors) - toxic diffuse parenchymal goiter.
 * 7) Myasthenia gravis (against acetylcholine receptors on neuromuscular discs).
 * 8) Primary biliary cirrhosis (against cells of the interlobular bile ducts of the liver).
 * 9) Nonspecific intestinal inflammation (IBD).

Systemic autoimmune diseases

 * 1) Collagenosis (lupus erythematosus, scleroderma, dermatomyositis).
 * 2) Rheumatoid arthritis.
 * 3) Sjogren's syndrome.
 * 4) Reiter's syndrome.

Viscerocutaneous collagenosis

 * Systemic autoimmune diseases. These are fibrinous interstitial inflammations.
 * They have nothing to do with collagen disorders - the name collagenosis was previously led to the finding that they can be treated with ACTH and corticosteroids.

A. Systemic lupus erythematosus (SLE)



 * Formation of several types of autoantibodies against various antigens (and the resulting diversity of disease symptoms): against nuclear antigens (ANF - Anti Nuclear Factors) such as ds-DNA, histones, RNA, against phospholipids, etc. - binding of antibodies to antigens leads to the formation of immunocomplexes, which are stored in various tissues and damage them (activation of complement, whose chemotactic components attract neutrophils, which release their lysosomal enzymes) - this is an immunopathological reaction type III.
 * It is characterized by the presence of hematoxylin bodies in the interstitium of damaged tissues, it is a histological picture of LE cells - granulocytes with large basophilic inclusion, which is the remnant of the phagocytosed damaged nucleus.
 * It mainly affects young women.


 * 1. Acute and subacute lupus erythematosus
 * Skin:
 * Red-violet erythema + photosensitivity. Under the influence of UV radiation or other skin damage, autoantigens are released into the circulation, where autoantibodies bind to them and immunocomplexes are deposited in the basement membrane of the epidermis.
 * Especially in places not covered by clothing (butterfly erythema on the face, palms and fingertips).
 * Microscopically fibrinoid necrosis of the corium just below the epidermis, narrowing of the epidermis, vacuolar degeneration to disintegration of the cells of the basal layer (subepidermal vesicles), thickened basement membrane.


 * Vessels: Fibrinoid necrotic generalized vasculitis (analogy of PAN, but also affects smaller vessels).
 * Kidneys: Focal glomerulonephritis.
 * Heart: Libman-Sacks endocarditis (atypical verrucous endocarditis) - non-bacterial endocarditis, mainly affecting the ventricular area of ​​clogged valves and the wall endocardium.
 * Seroses: Non-purulent polyserositis (pleuritis, pericarditis).
 * Joints: Arthritis, especially of the small joints of the hand.
 * Blood: Disorders of hematopoiesis (cytopenia) and coagulation (thrombosis).


 * 2. Chronic lupus erythematosus
 * It is characterized mainly by skin involvement (foci with inflammatory erythema, follicular hyperkeratosis, scarring atrophy of the corium and periadnexal small cell infiltration), skin cancer is more common.

B. Scleroderma



 * Sometimes it also affects internal organs (lungs - more common lung cancers, GIT - often esophagus, muscle replacement with ligament - leads to stenosis and dysphagia, more common cancers, blood vessels - intimal thickening and circulatory disorders), has a limited and generalized form.

C. Dermatomyositis

 * It affects the skin, muscles and nerves, in the acute stage it resembles erythematosus, in chronic it rather resembles scleroderma.

Rheumatoid arthritis (polyarthritis progressiva)



 * Chronic disease of a large number of joints (usually symmetrical), conditioned by an immunopathological reaction type III (deposition of immunocomplexes - the so-called rheumatoid factor of IgM in binding with IgG antibodies – and immune responses to them - activate complement, whose chemotactic components attract polymorphonuclear cells – their enzymes cause disruption of the surrounding tissue), a common complication is secondary (AA) amyloidosis.
 * It has some features in common with rheumatic arthritis (heart disease, findings of rheumatic nodules), but the pathogenesis is different, it more often affects middle-aged women.


 * Clinical manifestations
 * It begins as morning stiffness and soreness of the joints of the hand and foot, gradually decreasing the range of motion until ankyloses and muscle contractures develop.
 * It is a permanently progressive disease that can lead to complete immobilization.


 * Microscopy
 * At each outbreak, the joint cavity is filled with serous to sero-fibrinous exsudate of low viscosity, mixed with polynuclear cells.
 * The synovial membrane is congested and permeated, with round cell cellulation (plasma cells form rheumatoid factor and immunoglobulins. The resulting immunocomplexes are deposited in the synovialis, cartilage and synovial fluid). The membrane later swollen (villous productive synovialitis) and extends to the cartilage like a pannus. The cartilage necrotizes and granulation tissue forms beneath it (reminiscent of osteoarthritis, but there are no osteophytes at the edges of the joint).
 * In the later stages, the synovialis smoothes out, the pannus turns into a thick fibrous membrane, fibrous and later bony ankylosis occurs, and osteoporosis develops around the joint, which later affects the entire bone.


 * Macroscopy
 * In the final stages, muscle contractures arise (mainly from limited joint movements due to pain), which leads to deformities of the limbs - the appearance of the hand is typical, where the contractures of the interosseous muscles create ulnar deviation of the fingers.

Sjogrenův syndrom

 * Klinický syndrom charakterizován xerostomií, xeroftalmií a revmatoidní artritidou, má formu:
 * 1) primární – postihuje exokrinní žlázy (slinné, slzné, potní, tracheobronchiální, žaludeční, vaginální);
 * 2) sekundární – navíc projevy kolagenóz (SLS, sklerodermie, polyarteritis nodosa, chronická polyartritida, Reynaudův syndrom), v 5–10 % při ní vzniká MALTom.


 * Typicky postihuje ženy kolem menopauzy.
 * Příčinou je zřejmě autoimunitní pochod charakterizovaný tvorbou protilátek proti cytoplasmatickým antigenům duktálního epitelu. Je zde možnost induktivní role sialotropních a lymfotropních virů.
 * Mikroskopicky stejný obraz jako myoepitelové sialoadenitidy (lymfoidní infiltráty kolem vývodů, které se zužují, jejich lumen zaniká a mění se v epimyoepitelové ostrůvky, vztah mezi oběma syndromy je blízký, ale u více než poloviny nemocných s myoepitelovou sialoadenitidou není xerostomie a/nebo xeroftalmie).

Reiterův syndrom
Tvoří jej triáda:
 * 1) negonokoková uretritida,
 * 2) postinfekční seronegativní artritida,
 * 3) konjunktivitida.

Současná léčba autoimunitních a alergických onemocnění

 * 1) Protizánětlivé léky (NSAID, steroidy);
 * 2) Blokátory mediátorů příznaků (antihistaminika, antagonisté leukotrienů a jejich receptorů, solubilní TNF-R…);
 * 3) Cyclosporin – imunosuprese;
 * 4) Plasmaferéza.

Experimentální léčba autoimunity a alergie

 * 1) Indukce tolerance – opakovaným perorálním podáním antigenu (probíhající klinická studie prevence DM I. typu – inzulin, terapie revmatoidní artritidy – kolagen typ II):
 * 2) * i.v. podáním antigenu;
 * 3) * opakovaným parenterálním podáváním nízkých dávek antigenu (klinická studie prevence DM I. typu – inzulin).
 * 4) Ovlivnění kostimulace (blokátory kostimulačních molekul).
 * 5) Antagonisté prozánětlivých cytokinů (jako IL-1, TNF) – TNF-αR.
 * 6) Genová terapie.
 * 7) Specifické ovlivnění průběhu na molekulární úrovni – blokátory efektorových molekul a jejich receptorů. Blokátory migrace lymfocytů do tkání.
 * 8) Imunoablace a autotransplantace CD34+ buněk – (klinická studie u pacientů v pozdních stadiích život ohrožujících autoimunitních chorob, např. lupus erythematodes, roztroušená skleróza, autoimunní hemolytická anémie, autoimunní trombocytopenická purpura aj.).
 * 9) Copolymer 1 (Copaxone), analog myelinu složený z – L-tyrosinu, kys. L-glutamové, L-alaninu, L-lysinu (roztroušená skleróza).

Related Articles

 * Autoimmune liver diseases
 * Systemic lupus erythematosus
 * Systemic scleroderma
 * Rheumatoid arthritis
 * Reactive arthritis