IMMUNOHEMATOLOGY (Latin immunis free, saved from something + hematology) — the section of immunology studying the diseases of blood connected with immunological reactions of an organism. And. has two aspects of researches: immunological and clinical. Immunol, aspect includes studying of antigens of erythrocytes, leukocytes, thrombocytes, proteins of a blood plasma, antibodies to these antigens and reactions between them which can be the cause patol, states. The wedge, aspect includes studying of clinic, diagnostic methods, prevention and therapy of the diseases of blood caused immunol, mechanisms.
In clinic hemolitic anemias, leukopenias, thrombocytopenia, a hemolitic disease of newborns and posttransfusion complications have the greatest value.
Opening of blood groups of the AB0 system (K. Landshteyner, 1900 — 1901), and is later than other systems of group antigens of erythrocytes, leukocytes, thrombocytes, proteins of a blood plasma (see. Blood groups ) had significant effect on development And. as sciences also made an invaluable contribution to understanding of a pathogeny of these diseases, their diagnosis, prevention and therapy.
Normal, as we know, at the person antibodies only to alien antigens are formed. However antibodies on the relation and to own, not changed antigens, i.e. true can be developed autoantibodies (see), with to-rymi connect emergence of many immunopatol. states. A classical example of an autoimmune disease is acquired hemolitic anemia (see). This disease was described by G. Hayem in 1898, and then F. Vidal with sotr. (1907) and A. Shoffar with sotr. (1908). However autoimmune genesis of the acquired hemolitic anemia received the confirmation only after Burmen, Dodd and L of an uta (To. Boorman, V. of Dodd, F. J. Loutit, 1946) applied Koombs's test to inspection of patients with hemolitic anemias (see. Koombs reaction ), allowing to reveal incomplete autoantibodies on a surface of erythrocytes (direct test). It was succeeded then to eluate autoantibodies from a stroma of erythrocytes and to prove identity them with the antibodies circulating in blood serum. Less often presence at serum of sick free autoantibodies to a nek-eye is possible to establish indirect breakdown of Koombs to antigens own» erythrocytes. Distinguish two types of autoantibodies which can take part in an origin of hemolitic anemia — cold and thermal. Antibodies of cold type are more active at low (to 20 °) to temperature, however they can show hypoactivity and at higher (30 — 32 °) temperature. Autoantibodies of thermal type are active at t ° 37 °, they belong hl. obr. to IgG.
The autoantibodies of thermal type found at the acquired hemolitic anemia are most often directed in relation to these or those antigens of system a Rhesus factor: e, with, E, D (see. Rhesus factor ). Thermal autoantibodies quite often meet in mix: anti-e and anti-c, anti-e and anti-D, anti-With and anti-D, as well as in other combinations.
Also cold-reactive antibodies which are usually full IGM hemagglutinins can cause the acquired autoimmune hemolitic anemia and contain often in a high caption. Generally it antibodies of anti-I, i.e. to the isoantigen I, very widespread among people, localized on a surface of erythrocytes. Antibodies of anti-i often found at persons with primary atipichesky pneumonia. Cases of the acquired hemolitic anemia caused and autoantibodies of cold type of anti-I were described. These antibodies often found at an infectious mononucleosis. Antibodies of cold type cause hemolitic crises during the cooling (a cold gemagglyutininovy disease). Positive direct test of Koombs turned out only with the erythrocytes taken from vessels of skin i.e. from the blood which was more cooled.
Clinically expressed rare option of rough destruction of erythrocytes after overcooling of an organism opened by J. Donath and K. Landshteyner in 1904 and which received the name of a paroxysmal cold haemoglobinuria is also caused by Cold autoantibodies which often have a specific focus to group antigens of erythrocytes of system P. Serum of the patient lyses the erythrocytes containing P1 and P2 antigens and does not react with erythrocytes of p or Pk.
During the cooling of this or that part of a body of an antibody of cold type can connect to erythrocytes and activate a complement. At temperature increase of an antibody from a surface of erythrocytes eluate, but a small part them, apparently, remains.
Optimum hemolysis is observed if the first component of a complement (C1) is present with antibodies at a cold phase of reaction. The C4 component can interact both in cold, and in a warm phase, and C2-and SZ-components are active only in a warm phase.
The paroxysmal cold Haemoglobinuria can arise not only as a result of a disease of syphilis as earlier assumed, but to have also other etiology (measles, parotitis, etc.). The mechanism of death of erythrocytes, sensibilized autoagglyutininam, is quite difficult and not quite is still clear. The direct intravascular hemolysis occurs only under the influence of hemolysins. It is established that fixing of autoantibodies on a surface of erythrocytes interferes with use of glucose by them. At the same time there is an activation of some cellular enzymes, in particular an alkaline phosphatase. These biochemical, shifts break properties of membranes of erythrocytes, promote their spherocytosis and intravascular agglutination. The agglutinated erythrocytes are late in a spleen, a liver, marrow, limf, nodes where they are exposed to sequestration, and then a lysis by fabric macrophages. Assume also that process of sequestration of erythrocytes is promoted by B-lymphocytes, to the Crimea they stick as sockets.
The question of the reasons and mechanisms of formation of autoantibodies remains still poorly studied, and all offered explanations have still hypothetical character. Consider [G. F. Springer, 1963] that some forms of the acquired hemolitic anemias result from antibody formation to the exogenous antigenic substances having looking alike antigens of erythrocytes i.e. there are cross reacting antibodies which lead to destruction of erythrocytes. Existence of antigens or antigenic determinants, the general both for microbes, and for body tissues is experimentally proved. However it is difficult to explain why there is an overcoming immunol, tolerances to antigens which are normal available to immunocompetent cells (see). Normal, as we know, the organism answers with an immune response only the antigenic substances which are products of alien genetic information.
F. Burnett (1969), and also Dameshek (W. Dameshek, 1963) consider developing of autoimmune hemolitic anemia as a result of vegetative mutation of immunocompetent cells and emergence of the clone of cells deprived immunol, tolerances to own antigens. In usual conditions mutant cells eliminirutsya by the cellular system of T lymphocytes exercising genetic control of cellular structure. During the easing immunol, functions of an organism, including cellular system, there will be a development of autoimmune hemolitic anemia. It is possible to explain with this way frequent development of a disease as accompanying hron. to a lymphoid leukosis, a lymphogranulomatosis, an agammaglobulinemia and other diseases at which the immune system is weakened (V. P. Dygin, 1964). There are data indicating a certain communication of an autoimmune disease with a hereditary factor, in particular with the gene of an immunoreactivity (Ir) defining expressiveness of an immune response and also the genes controlling histocompatibility antigens and factors of a complement which are located together on one C6 to a chromosome.
According to other hypothesis, exogenous substances, being adsorbed on a surface of erythrocytes, can induce antibody formation to these alien antigens. Waste products of bacteria, viruses, helminths can be such exogenous antigens. Erythrocytes on which surface such substances are adsorbed can become object of influence of antibodies and a complement and to be the cause of hemolysis. Gaptenny substances can report new antigenic specificity to erythrocytes, leukocytes, thrombocytes. Many medicines have, apparently, the same mechanism of immunogene action.
Enzymes of viruses and bacteria can affect erythrocytes of in vitro and in vivo and to lead to emergence on their surface of antigens, new, alien for an organism, in relation to the Crimea the antibodies capable to agglutinate and dissolve the erythrocytes changed thus by means of a complement are formed. Sialidazny activity of viruses and bacteria can be an example of it, a cut in cells new antigens of Tomsen result, and then there are also antibodies corresponding to them. However in the presence of such mechanism true autoantibodies do not arise [P. Grabar, 1963] as change of antigenic substance is connected with influence of the exogenous agent and the organism answers with an immune response the antigens this changed, again arisen, as well as any other alien antigenic substances. At the true autoimmune acquired hemolitic anemia of an aberration concern not antigens of erythrocytes, and immunoeducational function of an organism.
True autoantibodies are directed to the normal, genetically determined for this or that individual antigens which specificity quite often manages to be defined. At the hemolitic anemias connected using medicines, and also caused by bacteria, viruses etc., elimination of exogenous factors leads to elimination of hemolitic anemia. True autoimmune diseases can be inhibited to some extent only at impact on immunoeducational function of an organism, napr, immunodepressants. Antibodies to the new antigens which arose in cells under the influence of physical. - chemical or biol, factors, is the normal immune response of an organism directed to release from the changed cells and fabrics which became alien. True autoimmune reactions from beginning to end — deep pathology, an aberration, they do not promote preservation of a normality of the individual. Autoimmune hemolitic anemia can accompany hron, to a lymphoid leukosis, a lymphogranulomatosis and others gematol, to the diseases which are characterized by proliferation of an adenoid tissue (V. P. Dygin, 1964).
In relation to leukocytes agglutinins, lysines, opsonins, pretsipitina and cytotoxins are found. At blood of many patients with a leukopenia there are anti-leukocytic antibodies. In addition to leykopenichesky states, independent in nozol, the relation, antileukocytic antibodies are found also at a number of symptomatic leukopenias, at aleukemic forms of leukoses, a multiple myeloma, a lymphogranulomatosis, Markiafava's disease — Mikeli, the disseminated lupus erythematosus, aplastic anemia (M. S. Dultsin, etc., 1958).
Development of a leukopenia in the presence of anti-leukocytic antibodies is connected with agglutination of leukocytes of peripheral blood and their subsequent death (obviously, in a spleen). Belonging of antileukocytic antibodies to autoantibodies with persuasiveness is not proved. The mechanism of emergence of antileukocytic antibodies as well as anti-erythrocyte, it is still insufficiently studied. Slightly more clearly, probably, the situation with formation of allergic anti-leukocytic antibodies is. As a classical example of the disease connected with such antibodies serves the amidopirinovy agranulocytosis. Are described also agranulocytoses (see), caused by streptocides. In similar cases the leukopenia develops usually after repeated administrations of drug, and at its cancellation quickly disappears. According to Zh. Dosse, the medicine plays a role of hapten which, connecting to cellular protein, forms the complex antigen causing a sensitization of an organism. Proof immunol. (allergic) genesis of some medicinal leukopenias does not exclude existence and purely toxic leukopenias. Others amidopirinovy agranulocytoses meet more often (see. Agranulocytosis ).
Along with immune hemolitic anemias and leukopenias also existence immunol, trombotsitopeniye is not subject to doubt. Among antithrombocytic antibodies distinguish lysines, agglutinins, pretsipitina, allergic antibodies. Hemotransfusion or plasmas of patients with a Werlhof's disease to healthy faces is followed by falling of number of thrombocytes, and sometimes and emergence of hemorrhages. Transfusion of a platelet concentrate by such patient is followed bystry (especially at acute forms) by disappearance from a circulatory bed of the poured thrombocytes. Detection of antithrombocytic antibodies testifies to the immune mechanism of some forms of Werlhof's diseases.
Allergic thrombocytopenia on the pathogeny are identical to allergic leukopenias. For the first time they were described by Granzhan (L. Grand jean, 1948) in connection with treatment by quinine are in more detail studied by Ekroyd (J. Ackroyd, 1949) at the patients receiving sedormid. Cases of a Werlhof's disease in connection with an allergy to quinidine at and to other drugs are known.
Autoimmune defeats of system of blood can be not only isolated, but also combined; hemolitic anemia can be in a combination with thrombocytopenia (see. Fischer — Evans a syndrome ).
At the heart of some forms of disturbance of coagulability of blood caused by deficit of its separate components the autoserotherapy against proteins of plasma can lie. Antibodies at connection with factors of coagulation can cause their deficit. Formation of autoantibodies against antigens of a blood plasma is established also at some negematol. diseases. Antibodies against antigenic determinants of heavy chains of IgG (system of Gm alloantigens) often are found in patients lupus erythematosus (see) and pseudorheumatism (see).
A number of the facts allows to speak about an essential role of immune mechanisms in vascular pathology. Honor allergic genesis of a hemorrhagic vasculitis (Shenleyn's disease — Genokh) in anybody does not cause objections (V. A. Nasonova, 1959).
Especially difficult autoimmune disorders are found at an acute lupus erythematosus. For it existence of autoantibodies to kernels of the leukocytes causing characteristic morfol is considered pathognomonic. phenomenon of LE (phagocytosis of kernels of leukocytes). Often find in such patients at the same time antibodies to erythrocytes, thrombocytes and leukocytes.
The complexes circulating in blood of various origin antigen — an antibody can damage walls of vessels and be, therefore, the cause of many patol, states — diseases of cell-bound immune complexes.
The big place in And. occupy the problems connected with immunol, the conflict developing in the course of pregnancy between an organism of mother and a fruit. The first paid attention to communication of obstetric complications with Rh-Hr antigen F. Levin and Stetson (Ph. Levine, R. Stetson, 1939).
It is established that in an organism of the Rh-negative woman pregnant with a Rh-positive fruit, Rh antibodies are developed. The sensitization of an organism of mother to Rh-Hr antigen occurs owing to passing through a placenta of nek-ry quantity of erythrocytes of a fruit.
Rh antibodies, being, as a rule, immunoglobulins of a class G, get through a placenta into an organism of a fruit and cause damage of erythrocytes, and together with them and vitals: hemopoietic fabric, liver, brain. Most often monovalent antibodies to antigen D are the reason of a hemolitic disease of newborns. Cases of the hemolitic anemia caused by antibodies to antigens with With, Cw, E, Ew, e, K, Fya, Jka, S, s are described, however. Nek-roye in development of a hemolitic disease of newborns also immune antibodys anti-And, matter Anti-century.
Knowledge of an etiology and pathogeny of hemolitic anemia of newborns allowed to develop a way of immunoprevention. It consists in introduction to the woman in labor of protivorezusny gamma-globulin in the first days after the birth of the Rh-positive child. Antirezusny gamma-globulin promotes bystry removal from an organism of the woman of alien erythrocytes of a fruit thanks to what there is prevention of an active sensitization of an organism to Rh-Hr antigen (see. Hemolitic disease of newborns , Rhesus factor ).
As the reason immunol, the conflict at pregnancy antigens of leukocytes can serve. In 1960 Mr. of Laledzari, Nussbaum (P. Lalezari, M. Nussbaum) and sotr. studied serum of the woman, at a cut newborn children of the 3rd and 4th pregnancies within 2 — 2,5 months had a neutropenia). Decrease in quantity of neutrophils at the same time reached 155 — 135 cells in 1 mm3. Serum of the pregnant woman agglutinated leukocytes of the husband and children and did not react with own leukocytes. The research of serum showed existence in it of leukoagglutinating antibodies against antigens of granulocytes. It is established that the newborn under the influence of maternal antibodies to antigens of granulocytes (NA — NB system) can have a neutropenia and cause the raised susceptibility of the child to an infection.
The role of antibodies to antigens of the HLA system in development of pathology of pregnancy still is finally not found out though there are instructions on possibility of the abortions and premature births caused by them. Antibody formation of anti-HLA as a result of repeated pregnancies is undoubted, however.
An important place in And. occupy the problems connected with hemotransfusion (see). Group antigens of blood can play a big or smaller role in development posttransfusion immunol, complications. Hemotransfusion can be carried out only from the donor having an identical or compatible blood group with the patient. However even in these conditions as a result of repeated transfusions immune antibodys to one or several antigens which are available in donor blood and absent at the recipient can be formed. In the immunizatsionny relation antigen D of system a Rhesus factor is represented to the strongest. The modern transfusiology provides therefore hemotransfusion and its components taking into account a blood group AB0 and a Rhesus factor accessory of the donor and recipient.
Existence in plasma of the recipient of antierythrocyte antibodies, and in erythrocytes of the donor of antigen of the corresponding specificity can cause an acute intravascular hemolysis of erythrocytes which is expressed in a haemoglobinaemia, a haemoglobinuria, a bilirubinemia, jaundice, damage of kidneys and other symptomatology. The posttransfusion complication can be caused by natural antibodies anti-And yes anti-In the recipient at wrong transfusion to it incompatible blood. However and antibodies of the «universal» donor 0(I) - groups at hemotransfusion in a large number and with a high caption of isohemagglutinins can be the cause of a posttransfusion complication.
Danger of development immunol, the conflict can be connected with antibodies to antigens Le, P, MNSs, etc. In the Lewis system the greatest value is played by the anti-Lea of an antibody meeting with the frequency of 0,1 — 0,5% of population at the persons Le (and - in-), i.e. free of factors of Lea, Leb [P. Mollison, 1972].
Antigens of erythrocytes of various allogenic systems have unequal ability to lead to an isosensitization and immunol, to the conflict at hemotransfusion. On the basis of a research of a large number of serums of patients it was shown [M. A. Umnova (1976); Salmon (S. Salmon), 1961] that antigens of erythrocytes on sensitizing power can be located in the following decreasing order: D, With, with, E, K, Jka, Fya. The sensitization against other antigens meets much less often.
The prevention immunol, the conflict at patients, sensibilized to antigens of erythrocytes, is reached by individual selection of the donor by means of indirect test Koombs and hemotransfusion, free of in erythrocytes of antigen, against to-rogo the patient has antibodies.
Compliance of antigens of erythrocytes, and in particular the AB0 systems of the donor and the recipient, is a necessary condition also at allogenic transplantation.
The wedge, materials point to very importance of antigens of leukocytes in transfusiology. Repeated hemotransfusions lead to formation of antileukocytic antibodies. The sensitization to histocompatibility antigens is found after 6 or more hemotransfusions. At hemotransfusion HLA-A antigens have the greatest value: 1, 2, 3, 9, 10, 11; HLA-B: 5, 7, 8, 12; W: 15, 35, 40; NA1, NA2 and others, the occurrences having considerably bigger frequency in populations, than other histocompatibility antigens (see. Immunity transplant ).
Introduction of allogenic leukocytes to an organism of the recipient, sensibilized to them, can be followed by development of the not hemolitic transfusion reactions which are characterized by temperature increase, a fever, retrosternal pains, weakness, etc. At the same time there is a damage of the poured leukocytes and thrombocytes without noticeable therapeutic effect. Transfusion reactions of not hemolitic type are the main reason complicating carrying out repeated repeated hemotransfusions, which is correctly picked up for antigens of erythrocytes.
The most justified measure of the prevention of transfusion reactions at patients with antileukocytic antibodies is transfusion by it of blood and its components taking into account not only antigens of erythrocytes, but also leukocytes of the HLA and NA — NB system (see. Blood groups ). It is about the choice of the donor of a similar phenotype on histocompatibility antigens among the contingent of previously typed persons.
Considering a large number of possible phenotypes of histocompatibility antigens, use of blood and its components from the immediate family of the patient — the father, mother, children having similarity of HLA antigens on a haplotype and also brothers and sisters who in 25% have the HLA antigens identical with the patient is proved (E. A. Zotikov, 1976).
Apply transfusion of the washed erythrocytes, i.e. the component of blood deprived of leukocytes, thrombocytes and the plasma containing histocompatibility antigens to prevention of posttransfusion complications. Especially useful it appeared in transplantology. Use of such erythrocytes before transplantation is not followed by a sensitization to histocompatibility antigens and formation of the cytotoxic antileukocytic antibodies having adverse effect on a transplant.
Other form of incompatibility at hemotransfusion are immunol, the reactions caused by action of anti-plasma antibodies. The anaphylactoid nature of the reaction which is followed by an itch of skin and small tortoiseshells it is typical for this form of incompatibility [Blamberg (V. of Blumberg), 1964].
Antibodies are directed generally against heavy chains of IgG and IgA. The main method of the prevention immunol, the conflict at patients, sensibilized to proteins of plasma, is transfusion of the washed erythrocytes or the defrozen blood.
Establishment immunol, mechanisms which are the cornerstone of many diseases of blood opened new opportunities of their diagnosis, prevention and therapy.
Questions I. are widely discussed on the international congresses on hemotransfusion; the 12th international congress took place in Moscow in August, 1969.
In 1938 the International society on hematology and transfusiology was organized. In many republics of the Soviet Union in-t in Moscow function in-you hematology and hemotransfusion, including and central.
In 1956 the «Problems of Hematology and Hemotransfusion» magazine is founded.
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Item H. Jambs, E. A. Zotikov, Yu. I. Loriye.