Pathophysiology_FULL

18. The 1st type of hypersensitivity. The causes and mechanism of patient sensitization to etiologic factors. The basic diagnostic methods and possible methods of treatment.

Hypersensitivity – abnormal or excessive responsiveness to a sensitizing agent, usually requiring previous exposure.

•The cause of allergy is an allergen or hapten - the such substances (mainly proteins, lipoproteins, glycoproteins) that strongly elicit Th2 cells, IgE-AB and thus atopic/allergic diseases.

•The conditions. Genetic predisposition, pollution, influence of strong allergens (the ambrosia), state of barrier tissues (permeability) and immune system, hyperreactivity of an organism, treatment with vaccine and serum.

Pathogenesis

•I stage – the immunological or stage of sensitization. (AB production).

Cooperation of All + APC + Th2 + B-cell + IL-4  presentation and recognition the All  proliferation of Th2,  synthesis of IL-4 with Th2, proliferation and differentiation of B-cell into plasma cells and switching over Ig synthesis from IgM to IgE  accumulation of IgE–AB which attach to their target cells. It takes minimal 7-14 days. An organism with target cells armed with IgE-AB – an active sensitized organism.

APC – dendritic cells, macrophages and B-lymphocytes

1.Primary contact of allergen with APC, wearing MHC-II

2.APC present the products of antigen transformation to CD4+-cells type 2

3.Formation of membrane complex with Th2-lymphocytes via T-cell receptors and CD3+-surface antigen synthesis of IL-4,3,13

4.Activation of Th2-cells by IL-4 and IL-13 synthesis of IgE and the expression on B- cell membranes  B-cells to plasma cells + secretion of monoclonal antibodies specific to the allergen

•II stage – the pathochemical stage. (Mediator release)

Anaphylactic mast cell degranulation.

The bridging of IgE molecules activates signal transduction pathways  activation of tyrosinkinases biochemical reactions: 1)  of cAMP, then after spending cAMP in proteinkinases activation - of cAMP; 2)  of endoand exogenious Ca++myosin activation, moving of granules and degranulation = secreting of granules with preformed (primary) mediators; 3) phospholipase A2 activation  synthesis and secretion of lipid mediators (secondary mediators); 4) synthesis and secretion of cytokines.

This leads to appearance of many active substance in an organism in some minutes after re-exposure to the specific All.

•III stage – the pathophisiological stage or stage of clinical sings and symptoms.

Mediators 1) increase vascular permeability (edema), 2) induce vasodilation (hyperemia), 3) irritation of sensitive nervous endings (itching, sneezing, cough), 4) mucus gland secretion, 5) smooth muscle spasm, 6) inflammation, APR.

Skin reaction – hives: blister, redness, itching.

Nasal and conjunctival reaction– edema, redness, itching, sneezing, mucus secretion. Lungs reaction – shortness of breath due to airway narrowing (edema, mucus and spasm in bronchi), cough.

Anaphylactic shock (systemic reaction) - shortness of breath, blood pressure, hives, loss of conscious.

Diagnosis

•1. Anamnesis/history (allergologic anamnesis).

•2. Skin tests.

•3. Provocative tests.

• 4. Laboratory methods – RIST (radioimmuneadsorption test – for total IgE), RAST (radio-allergoadsorption test – for specific IgE), IFA/ ELIZA (enzyme blood serum test for total IgE).

•5.  eosinophils in the blood.

•6. Analysis of clinical signs and symptoms.

Main principles of treatment of atopic diseases.

•1.Exclusion of causal allergen contacts.

•2. ASIT – allergen-specific immune therapy.

•3. Antihistamine agents (RH1-blockers).

•4. Leucotriene receptor antagonists.

•5. Drugs that  activity and degranulation of target-cells (mast cells) - Ca++ , cAMP.

•5. Anti-inflammatory drugs (glucocorticoids).

19.Type III of hypersensitivity reaction. Diseases belong to this type of hypersensitivity. The stages and their pathogenesis.

Features.

1. AB belong to IgM or IgG.

2.In the norm: immune complexes (IC) with such type of Ig (opsonins) undergo phagocytosis and disappear. At III type: they suppose overload or intrinsic dysfunction of mononuclear phagocytes or complement system. So, IC circulate in the body for a long time – circulating immune complexes (CIC).

3.CIC are formed in slight AG excess often.

4. CIC are soluble but can precipitate and deposit in tissue (IC in situ), typically in vessel walls.

5.The sizes of CIC are “intermediate” – enough small to stay in a solution and enough large to “stuck, lodge” on endothelial site of basement membrane (< 1000000 D) and such CIC are hardly phagocytosed.

6.The AG may be exogenous (foreign protein) and endogenous (e g DNA molecules).

Diseases belong to this type of hypersensitivity

1.Systemic autoimmune diseases

Rheumatoid arthritis

Systemic lupus erythematous

Dermatomyositis

Polyarteritis nodosa

2.Local immune-complex diseases

Immune vasculitis

Autoimmune glomerulonephritis

Farmer’s lung

Autoimmune orchitis

Sympathetic ophthalmopathy

3.General reaction of the organism in the form of acute serum sickness

Pathogenesis

Stage II – stage of pathochemical reactions.

After a forming of the AG-AB complex this complex activates the comlement system through the classical pathway and the first mediators appear:

1) С3а, С5а – anaphylatoxins and chemoattractants, С3b – opsonins, then after leukocytes activation – 2) toxic oxygen products, the lipid mediators - PAF, LT, PG, hydrolases, cytokines, then 3) the other mediators (histamine, bradykinin).

Stage III – pathophysiological.

CIC have the favored sites for precipitation: small blood vessels (vasculitis  thrombosis necrosis), skin (rush), heart, joints, serous surfaces. If the CIC are deposited locally  mediators and leukocytes will produce locally immune inflammation; when CIC are deposited in many organs  generalized form of disease. Activated leukocytes produce Il-1, Il-6, TNF  development of APR.