CLINICAL IMMUNOLOGY CLINICAL IMMUNOLOGY CLINICAL IMMUNOLOGY - DISEASES OF IMMUNE SYSTEM CLINICAL IMMUNOLOGY - DISEASES OF IMMUNE SYSTEM Clinical immunology is a separate field of human medicine. It represents research, diagnostics and therapy of diseases of the immune system. Many of primary diseases is often associated with disorders of the immune system. DISEASES OF THE IMMUNE SYSTEM DISEASES OF THE IMMUNE SYSTEM IMMUNODEFICIENCIES disorders of one or more parts of the immune system it leads to a decreased activity of the immune system primary, secondary HYPERSENZITIVITY local or systemic immune reaction leading to tissue damage mediated by antibodies, cells or immune complexes 1st, 2nd, 3rd, 4th type AUTOIMMUNE DISEASES specific immune reaction against self-antigens leading to damage systemic, organ-specific LYMPHOPROLIFERATIVE DISEASES tumor diseases originating from cells of the immune system leukemias, lymphomas, myelomas, gamma-pathies IMMUNODEFICIENCIES IMMUNODEFICIENCIES Disorders of one or more parts of the immune system Common clinical signs include chronic or recurrent infections caused also by organisms in normal circumstances less pathogenic
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CLINICAL IMMUNOLOGYCLINICAL IMMUNOLOGY
CLINICAL IMMUNOLOGY -DISEASES OF IMMUNE SYSTEM
CLINICAL IMMUNOLOGY -DISEASES OF IMMUNE SYSTEM
Clinical immunology is a separate field of human medicine. It represents research, diagnostics and therapy of diseases of
the immune system.
Many of primary diseases is often associated with disorders of the immune system.
DISEASES OF THE IMMUNE SYSTEMDISEASES OF THE IMMUNE SYSTEM
IMMUNODEFICIENCIESdisorders of one or more parts of the immune system it leads to a decreased activity of the immune system
primary, secondary
HYPERSENZITIVITYlocal or systemic immune reaction leading to tissue damage mediated by antibodies, cells or immune complexes
1st, 2nd, 3rd, 4th type
AUTOIMMUNE DISEASESspecific immune reaction against self-antigens leading to damage
systemic, organ-specific
LYMPHOPROLIFERATIVE DISEASEStumor diseases originating from cells of the immune system
leukemias, lymphomas, myelomas, gamma-pathies
IMMUNODEFICIENCIESIMMUNODEFICIENCIES
Disorders of one or more parts of the immune system
Common clinical signs include chronic or recurrent infections caused also by organisms in normal circumstances less
Numbers of syndromes have been described. Some of them have been described on genus level, in other only clinical signs.
Based on type of affection, they can be divided to combinedT lymphocyteB lymphocyte and antibodiesphagocytosiscomplement
Prevalence of primary immunodeficiencies is low.
Severity of clinical signs depends on type of impairment
IMMUNODEFICIENCIES IN DIFFERENT PHASES OF CELL DEVELOPMENT
IMMUNODEFICIENCIES IN DIFFERENT PHASES OF CELL DEVELOPMENT
lymphoidprecursor
myeloidprecursor
progenitorcell
LAD SYNDROME
GRANULOCYTOPATIC SYNDROME
CHÉDIAK-HIGASHI SYNDROME
macrophage / monocyte
granulocyte
SCID
SCID
AGAMMAGLOBULINEMIA SELECTIVE Ig DEFICIENCIE
plasma cell
preT
preB B
T
TYPES OF PRIMARY IMMUNODEFICIENCIESTYPES OF PRIMARY IMMUNODEFICIENCIES
Combinedsevere impairment, whole cell types are missing, dysgenesis of organs, death during first weeks of life
T lymphocytesevere impairment, systemic infections, defects mainly in functional characterization of T lymphocytes
B lymphocytelow level of immunoglobulins - agammaglobulinemia is rare, selective deficit of particular isotypes is more frequent IgA deficiency - respiratory, enteral or cutaneous infections
Complementmainly impairment of C3 fraction, severe bacterial either systemic or organ infection
Phagocytosismany syndromes, impairment of different character, often chronic or recurrent purulent infections
biochemical examinations (level of immunoglobulins)
Laboratory examinations of immunological profile
CLINICAL SIGNS OF IMMUNODEFICIENCYCLINICAL SIGNS OF IMMUNODEFICIENCY
Chronical or recurrent infections
Infections with unusual or less pathogenic agents
Incomplete removing of infectious agents among clinical episodes
Weak response to therapy with antibiotics or sulphonamides
THERAPY OF IMMUNODEFICIENCIES THERAPY OF IMMUNODEFICIENCIES
THERAPY OF PRIMARY IMMUNODEFICIENCIESusually does not exist - removing of animals from breedingbone marrow transplantationsubstitution with gammaglobulins
THERAPY OF SECONDARY IMMUNODEFICIENCIESremoving of underlying causes (if it will work)therapy of infectious diseasessupplementation with gammaglobulinsimmunostimulation
HYPERSENSITIVITY OF 1st TYPEHYPERSENSITIVITY OF 1st TYPE
early hypersensitivity
induced by allergen and modulated by Th2 type reaction
mediated by IgE antibodies, crucial cell is mast cell
IgE binding to Fc-receptor on mast cells, their cross-linking leads to degranulation and to releasing of inflammatory mediators
early mediators - histamine, serotonin, PAF
late mediators - metabolites of arachidonic acid -prostaglandins, leukotriens
atopy = genetically mediated hypersensitivity of 1st type to inhaled or swallowed allergen
anaphylaxis = acute systemic hypersensitive reaction of 1st
type
keratinocytesLangerhan´s cell
ALLERGEN
IgE
IL-8Th2
B
IL-4
IL-5
HYPERSENSITIVITY OF 1st TYPE
days to
years
NEW EXPOSITIONSENZIBILISATION LOCAL REACTION
SYSTEMIC SHOCK
minutes(days)
SENZIBILISATION TO ALLERGIC REACTION
fosfolipases
ARACHIDONIC ACID
fosfolipids of cell membranes
5-lipooxygenase
5 HPETE
cyklooxygenase
PGG2
LTC …LTD ...LTE
LEUKOTRIENS4 4 4 PGD PGE PGF
PROSTAGLANDINS2
PROSTACYKLINES
TROMBOXANES2 2a
METABOLISM OF ARACHIDONIC ACID ANAPHYLACTIC SHOCKANAPHYLACTIC SHOCK
acute systemic reaction caused by sudden release of inflammatory mediators (histamine, serotonin)
mechanisms of action:excessive contraction of smooth muscles (bronchoconstriction)vasodilatation, increased permeability of veinsincreased mucus secretion
it results in hypovolemic shock, edema of subcutis and organs, general hypotension, but pulmonary hypertension
ANAPHYLACTIC SHOCK IN DIFFERENT ANIMALSANAPHYLACTIC SHOCK IN DIFFERENT ANIMALS
Polyfactorial charactergenetical predispositioninfectious agentseffect of environmentother immune-mediated diseases
Dysregulation of immune systemdysregulation of Th1 x Th2dysregulation of selection during differentiation
Changes of autoantigens or their presentation uncovering of so far inaccessible (cryptic) antigensantigenic mimicry with infectious antigens polyclonal activation by superantigens
ALLERGIC AND AUTOIMMUNE DISEASES
ALLERGIC AND AUTOIMMUNE DISEASES
ALLERGY ALLERGY
Allergy is frequent in animals and its importance increases
dogs – mainly skin diseases
cats – respiratory and skin diseases
horses – mainly respiratory diseases
cattle, pigs – also present, various forms
ALLERGY ALLERGY
Allergy - type I.
Atopic dermatitis – inherited skin reaction to the environmental allergen
often in dogs, rare in cats breeds – many: Terrier, Shar-pei, Dalmatin, Retriever, etc.marked pruritus, seasonalappears within 3 years of age
Flea bite allergythe most common allergy in dogs haptens of flea saliva bind to skin collagen - I. a IV.typemarked pruritic seasonal disease
ALLERGY ALLERGY
Allergic rhinitis or bronchitis- in dogs, horses – not common
Astma bronchiale- in cats
Chronic obstructive pulmonal disease (COPD)(hypersensitive pneumonitis) – in horsesreaction to the mold spores (arthropods, pollen)
new classification:RAO - recurrent airway obstruction
IAD - inflammatory airway disease
RAO – old horses, IAD yang racing horses
ALLERGY ALLERGY
Allergy of various types
Food allergy (I., III. IV. typ) – in all species– with different signs) -
Gluten enteropathy – in Irish Setters
Allergy to to the drugs or vaccines (I., III., IV. typ)- antibiotics, sulphonamides, hormons, vaccines
Sarcoidosis – granulomatous disease in horses(III. and IV. type, probably papillomaviruses), polyarthritis, erythema nodosum, uveitis
ALLERGY ALLERGY
Allergy type III.
Glomerulonephritis – often, reaction to the allergens, infection (and autoantigens) - streptococcus, staphylococcus, Feline peritonitis, infectious anaemia of horses
Vasculitis – reaction to the various antigens
Alergy type IV.
Kontact dermatitis – in various species- local reaction to drugs or chemicals
CAUSES OF AUTOIMMUNE DISEASES DEVELOPMENT
CAUSES OF AUTOIMMUNE DISEASES DEVELOPMENT
Polyfactorial charactergenetical predispositioninfectious agentseffect of environmentother immune-mediated diseases
Dysregulation of immune systemdysregulation of Th1 x Th2dysregulation of selection during differentiation
Changes of autoantigens or their presentation uncovering of so far inaccessible (cryptic) antigensantigenic mimicry with infectious antigens polyclonal activation by superantigens
Patogenesisin dogs – German Shepherd, Poodle, Colie, Beagle, Irish Setter genetic predisposition with infection? and UV radiation cause dysbalance of the immune system, oligoclonal activation of B cells and production of autoantibodies against nuclear antigens
Signsfever answering to corticosteroids non-answering to antibioticsarthritis, glomerulonephritis, mucocutaneous leasions, myositis, anaemia, trombocytopenia, neutropenia
in human medicinedisease modified drugs (sulfasalazine, methotrexate)
nonsteroid antiinflamatorz drugs
intravenous immunoglobulins
IMMUNOLOGICAL ASPECTS OF TRANSPLANTATION
IMMUNOLOGICAL ASPECTS OF TRANSPLANTATION
TRANSPLANTATION IMMUNITY TRANSPLANTATION IMMUNITY
Transplantation is a transfer of cells, tissues or organs from one part of body to another or from one individual to another.
Transplantation reaction is based on genetic differences between donor and recipient
RELATIONSHIP BETWEEN DONOR AND RECIPIENTRELATIONSHIP BETWEEN DONOR AND RECIPIENT
autotransplantation – transfer within one organism
syngenic transplantation – transfer between two genetically identical individuals (inbred line)
alotransplantation – transfer between individuals of the same species with different level of genetic relationship
xenotransplantation – transfer between individuals of different species (for example from pig)
TRANSPLANTATION ANTIGENS AND REACTIONTRANSPLANTATION ANTIGENS AND REACTION
major histocompatible system – is a group of strong transplantation antigens – determine about intensity and speed of reaction
minor histocompatible antigens – are dispersed around whole genome – differences between them lead to slow graft rejection
transplantation reaction - is reaction of immune system against MHC (also to minor) antigens on donor cells
Graft versus host reaction (GVHR) – appears after transfer of immunocompetent cells
TRANSPLANTATION REACTIONTRANSPLANTATION REACTION
Recognition - (afferent phase)
direct – recognition of whole MHC alloantigens on strange cells
indirect – recognition of antigenic graft (MHC as well as minor histocompatible) using antigenic presentation to Th cells of donor
Central phase
Th lymphocyte – co-stimulation (CD28 - B7) polarization to Th1 will lead to acute phase, polarization to Th2 will lead to an antibody production and chronic phase
TRANSPLANTATION REACTIONTRANSPLANTATION REACTION
Effector mechanisms - (efferent phase)
Tc lymphocyte - cytotoxicity against cells expresing strange MHC I, with help of Th1 cytokinescytotoxic mechanisms: perforins, granzymes
NK cells – lack of self MHC I
Antibody production – cytotoxicity dependent on antibodies, complement activation
Result of transplantation reaction could be graft rejection
hyperacute – in the case when antibodies are present at the term of transplantation
acute – mediated by Th1 and cytotoxic cells
chronic – mediated by Th2 and antibodies
MEASURES IN TRANSPLANTATIONMEASURES IN TRANSPLANTATION
Selection of donors
Matching in blood group system
Matching (at least partial) in MHC antigens
Test for lack of antibodies (cross-match)
Suppression of transplantant reaction
Using immunosupresive treatment
Myeloablation in case of bone marrow transplantation
IMMUNITY AGAINST TUMORSIMMUNITY AGAINST TUMORS
ANTI-TUMOUR IMMUNITYANTI-TUMOUR IMMUNITY
Tumor disease appeared as a result of mutations in gens, which control cellular proliferation and differentiation.
Tumor antigens provokes immune reaction mainly of cytotoxic type. In some cases, they may escape for
attention of immune system.
TUMOR ANTIGENSTUMOR ANTIGENS
specific tumor antigensthey are not present on normal cells
molecules MHC I with abnormal fragments of cellular proteins
molecules MHC I with fragments of oncogenic viruses
abnormal forms of glycoproteins (glycosylation, sialylation)
idiotyps of myeloms and lymphomas
antigens associated with tumorsvthey may be present also on normal cells
oncofetal antigens
melanomic antigens
antigens of leukemic cells - CALLA
DEFENCE AGAINST TUMORSDEFENCE AGAINST TUMORS
majority of tumor antigens are antigenic but they are badly immunogenic
cytotoxicity mediated by Tc lymphocytes
presentation via MHC I
cytotoxicity mediated by NK cellslack of MHC I molecules on surface of tumor cells
macrofages infiltrate tumor tissuethey may increase vascularization and a tumor grow
they may induce cytolysis by TNFα or other soluble mediators
role of antibodies is unclear
ANTIBODIES IN DIAGNOSTICS AND THERAPY
ANTIBODIES IN DIAGNOSTICS AND THERAPY
POLYCLONAL ANTIBODIESPOLYCLONAL ANTIBODIES
Polyclonal antibodies are obtained from sera containing mix of immunoglobulins with various specifity
Polyclonal antibodies are obtained by collection of sera from different donors: reconvalescent sera or hyperimmune sera
For in vivo application we could use autologous or heterologous sera
Their using in diagnostics decreased
MONOCLONAL ANTIBODIESMONOCLONAL ANTIBODIES
Monoclonal antibodies are created in vitro from one clone of hybridoma cells.
They are targeted to one epitope.
Monoclonal antibodies play important role in diagnostics as well as in therapeutical protocols.