Odessa National Medical University Department of Normal and

Odessa National Medical University Department of Normal and Pathological Clinical Anatomy Lecture on the topic: Pathomorphology of the immune system. Reactions and mechanisms of hypersensitivity.

Immunogenetic organs § Organized lymphoid tissue is divided into primary (central) and secondary (peripheral) lymphoid organs. § The primary lymphoid organs are thymus and bone marrow. The thymus consists of several lobes, in every lobe the cortical and medullar zones are present. Epithelial cells are the basic structure elements of the lobe. These cells produce peptide hormones, which stimulate Tlymphocyte (or T-cells) differentiation.

§ Coming from the bone marrow to the thymus, prethymocytes (prethymic T-cells) are deposited in the cortical layer and then they migrate into the medullar layer. As they migrate, their differentiation takes place. Cells are being divided into T-helpers, T-killers, T-suppressors. Maturing of Blymphocytes (or B-cells) takes place in the bone marrow, and later they migrate to the secondary lymphoid organs. § The indicated stages of T- and B-lymphocytes maturing are called antigen-independent, i. e. they do not depend on contacts with the antigens.

§ To the secondary lymphoid organs belong lymphatic nodes, the spleen, lymphoid tissue of the mucous membranes. Interaction processes between the immunocompetent cells take place, i. e. objective immune reactions (or responces) are formed. § Alien or foreign agents, which have penetrated the bodily tissues, are caught by the lymphatic nodes. The lymphatic node is covered by a dense capsule of connective tissue under which the friable reticular tissue is located. This reticular tissue forms the border and medullar sinuses. Blymphocytes are found between the sinuses, Tlymphocytes (thymus-dependent zone) are in the paracortical zone.

§ If the lymphatic nodes are in rest the Blymphocytes form primary follicles in the B-zone. After an antigenic stimulation, B-lymphocytes form secondary follicles, where there is the dense ring of B-lymphocytes on the peryphery, and the gerninal center is in the middle, where macrophages and proliferating B-lymphocytes are found. Plasmatic cells are formed out of them which migrate to the lymphoid tissues of the medullar zone. § Under antigenic stimulation of the T-dependent zone, a well-expressed T-lymphocyte proliferation is observed in the T-zone of the lymphatic node.

§ Spleen (or lien) consists of white and red pulp. The lymphoid tissue forms the white pulp. B-dependent zone is a peripheral zone of lymphoid follicles; the T-dependent one is a periarterial zone. § Lymphoid tissue is associated with mucous membranes. It is located in the epithelium and does not have a connective tissue capsule. Lymphocytes are either diffusly spread or presented by diffuse accumulations together with macrophages and plasmatic cells. § Besides, humans have even more organized structures with well-formed follicles – such as pharyngeal, palatine, and lingual tonsils, Peyer's patches, and lymphoid structures of the appendix.

Types of the lymphocytes and their role in the development of the immunity reactions § Specific immune reactions (responces) are produced by the lymphocytes. The lymphatic nodes are mainly of two types of lymphocytes, which differ as to their origin and functional peculiarities: T- and B-lymphocytes, and natural killer-cells (NK-cells) in small quantity. § T-cells (lymphocytes) § The peripheral blood contains 65 -80% of all Tlymphocytes. These cells are divided into effectorcells and regulator-cells.

§ Effector-cells are killers which have specific cytotoxicity to the alien cells. T-killers destroy target cells without the help of antibody complement. T-cell receptor kinds with the antibody of the target cells, which is a signal to lymphocytes to discharge the substances that destroy the target cell. Besides, T-killers produce lymphokins, which activate and attract the macrophages, natural killers and other cells. § Subpopulation of T-cells, that is T-helpers and Tsuppressors, perform the main regulatory function. T-helpers stimulate the proliferation and differentiation of B-lymphocytes.

§ T-suppressors suppress the immune response. Activated T-suppresors suppress the T-suppresors activity and the immune response proper. § B-lymphocytes compose 8 -15% of all the lymphocytes of the peripheral blood. Blymphocytes formation takes place in the red bone marrow from the stem cell. Mature B-lymphocytes populate the secondary lymphoid organs. Under antibody influence and its interaction with Tlymphocytes and macrophages, B-lymphocytes start differentiating into lymphoblasts, divide and transform into young plasmatic cells. § The main function of the plasmatic cells which are the successors of B-cells is the synthesis which takes place without specific immunoglobulin (antibodies).

§ At present, 5 classes of immunoglobulin have been discovered and studied. They are: Ig. A, Ig. D, ig. E, Ig. M, Ig. G. § Natural killers or normal killers (NK-cells) comprise up to 5% of all the lymphocytes, and are formed in the red bone marrow from T-lymphocyte precursors. NK-cells mature in the red bone marrow and then migrate to different tissues. Their main function is cytotoxic effect toward an alien cell, including tumor cells.

Morphologic basis of the humoral and cell-mediated immunity § All living processes are supported by the constant functioning of the main physiologic systems including the immune one. The immune system functioning is manifested in 2 forms: § 1. Normal functioning § 2. Active functioning

§ So, 1. The immune system cannot rest, because old cells die, faulty appear, viruses and bacteria penetrate through skin and mucous membranes, they all get destroyed by the immune system cells. § 2. System active functioning is presented by the immune reaction of two types: § a. humoral immunity § and b. cell-mediated immunity

§ Humoral immunity reactions are responses of the immune system to a definite antibody, which is characterized by B-lymphocyte clone proliferation, their differentiation into plasmatic cells that synthesize immunoglobulins (antigens). § Cell-mediated immune response is formed as a result of a number of immunecompetent cell interactions and that leads to the clone filling with T-lymphocyte-effectors which are sensitized to that particular antibody.

Immunopathologic processes. Definition. Classification. § Immunopathologic processes are the ones the development of which is connected with the immunocompetent (lymphoid) tissues function. § Immunopathologic process may be a manifestation of: § 1. Immunogenetic disturbance (antigenic stimulation or immunedeficiency) § 2. Local immune reaction in the sensitized body, i. e. hypersensitivity reaction

§ So, immunogenetic disturbances may be connected with : § a) thymus § b) peripheral lymphoid tissue § They are connected with the two types of the immune reactions – humoral and cellmediated.

§ Thymus pathology is manifested by: § § § - aplasia - hypo- and dysplasia - atrophy - accidental involution - thymus and lymphoid follicles hyperplasia - thymomegalia

§ Aplasia – is the absence of the thymus; hypo- or dysplasia – the thymus is decreased in size, division between cortical and medullar substances and number of lymphocytes is decreased. These are congenital development defects, accompanied by the deficiency of cell-mediated immunity or combined immune deficiency. § Accidental involution is a quick decrease of the thymus mass and bulk under glucocorticoid influence in different stress situations, infections, intoxication, traumas. The majority of Tlymphocytes is subjected to disintegration (apoptosis).

§ Thymus atrophy develops as an unfavorable outcome of the accidental involution and is the reason for a few acquired immunedeficiency syndromes. § Thymomegalia is characterized by the parenchyma mass and bulk increase with the preservation of normal structure of the organ. Congenital thymomegalia, found in children, is accompanied by the development defects of the internal organs, congenital suprarenal and sexual gland dysfunction. In infectious diseases it is accompanied by lymphoid tissue hyperplasia. Production of the thymus hormones is decreased, cell-mediated immunity is disturbed.

§ Acquired thymomegalia is found in adults in chronic insufficiency of the suprarenal (adrenal) glands. Death cause in thymomegalia can be infectious diseases, while endocrine system disturbance can lead to sudden death in surgical intervention. § Hyperplasia of the thymus with the lymphoid follicles is typical for autoimmune diseases. Blymphocytes gather in the dilated intralobular perivascular spaces and lymphoid follicles appear. Thymus hormone production is decreased or increased.

Thymus of a child, low magnification

Thymus of an adult, low magnification

Bone marrow, high magnification

Changes in the peripheral lymphoid tissue § These changes are the most characteristic in antigenic stimulation and hereditary insufficiency. § In antigenic stimulation (sensitization), the macrophage reaction and lymphocytic hyperplasia develop with their subsequent plasmocytic transformation. Changes are supplemented by an increased microvascular permeability and interstitium edema. Lymphatic nodes are increased in size, plethora and edema develop; many plasmoblasts are found in the cortical layer of the light follicular centers and in the medullar zone.

§ The spleen is increased, plethotic, plasmatization of the red pulp in follicular peripheral zone is observed. If cell-mediated immune reactions develop in response to the antigen stimulation, so sensitized lymphocytes proliferate in the lymphatic nodes and spleen, T-zones become wider. § Hereditary insufficiency of the lymphoid tissue in the spleen is characterized by follicle size decrease, light centers are absent. Follicles and the cortical layer (B-dependent zones) are absent in the lymphatic nodes. These changes are characterestic of the hereditary immune-deficiency synderomes, connected with the humoral immunity defect.

Development mechanisms of the hypersensitivity reactions of the delayed-type and immediate type § At the second contact with an antibody, the immune system reacts upon it with a stronger immune response, the allergic or hypersensitivity reaction develops. § The same mechanisms of cellular interactions, as in the humoral and cell-mediated immunity reactions, lie in the basis of allergic reactions. § Hypersensitivity reactions are the local immune reactions in the sensitized body.

§ There are 5 mechanisms of the hypersensitivity reactions: § The 1 -st mechanism (anaphylactic allergy of the immediate type) – antibodies (reagent, Ig. E) are produced and fixed on the cell surface (on labrocytes, basophils), they specifically react with antibodies, that leads to the excretion of the biologically active substances called mediators. This is accompanied by the acute inflammation (rhinitis, allergic eruptions, bronchial asthma) development.

§ The 2 -nd mechanism (humoral cytotoxic immune reactions or cytotoxic hypersensitivity) is cytolysis, it may be provided by the complement, which is activated when an antibody is connected with an antigen, or with other antibodies. Examples of such type reactions are: reactions in blood transfusion, Rh-factor incompatibility (i. e. haemolytic disease of the newborn) intolerance to some drugs. § The 3 -rd mechanism is connected with the toxic action of the circulating immune complexes (also called: immune complex hypersensitivity) (antibody+antigen) on the cells and tissues, that leads to complement component action (for example: serum disease, Arthus phenomenon).

§ The 4 -th mechanism is stipulated by the effector k-cell (lymphocytes) – and macrophage action on the tissues. The sensitized T-effectors affect the antigens and cytolysis develops. Such mechanism is characteristic of allergy in infectious diseases. § The 5 -th mechanism is granulomatosis.

§ Some of the mechanisms are the expression of the humoral immunity, others of the cellmediated immunity. The reactions connected with the immunopathologic reactions of the humoral immunity are called immediate type hypersensitivity (ITH) reactions; those reactions, which are connected with the immunopathologic mechanisms of the cell-mediated immunity are called delayed-type hypersensitivity (DTH) reactions. Besides those, there also transplant rejection reactions.

Lymphatic node, low magnification

Lymphatic node, high magnification

Spleen, low magnification

Spleen, high magnification

Morphologic characteristic of the hypersensitivity reactions § Immediate type hypersensitivity reactions (ITH) – have the morphology of an acute inflammation. They develop quickly, and have alterative and exudate, and vascular changes, reparation processes are very slow. Alterative changes are expressed by the plasmatic infiltration, mucoid and fibrinois swelling, fibrinoid necrosis of the vascular walls. Fibrin, neutrophils, erythrocytes are found in the focus of the immune inflammation; fibrinous or fibrinous-hemorrhagic exudate is also observed.

Contact dermatitis

§ Proliferative reactions develop later, they are poorly expressed, but endothelium and perithelium proliferation exists. § ITH reactions in Arthus phenomenon (in sentisized animals after injecting all the corresponding antigen dose) § In human it arises in tuberculosis, syphilis, rheumatism, systemic lupus erythematosus, croupous pneumonia. § Delayed-type hypersensitivity (DTH) reactions. Two types of cells take part in this reaction; they are sensitized lymphocytes and macrophages.

Affection of salivary gland in Sjogren syndrome

Islet of Langerhans. Insulitis in diabetes mellitus of 1 st type. Lymphocytal infiltration suggests autoimmune affection

REJECTION OF TRANSPLANT § Prevalence of operations on transplantation of tissues (organs) has significantly increased in clinical practice for the last two decades. Presently operations are successfully conducted on transplantation of cornea, skin and bones. Transplantation of kidneys is executed with high success in many large medical centers. § Transplantation of heart, lungs, liver and marrow are still experimental procedures, but success of these operations is increased every day.

§ Factors, limiting transplantation of tissues, are immunological reactions against the transplanted cells and presence of the proper donor organs. § Autotransplantation does not cause the immunological reactions of rejection, which is transplantation of the patient's own tissues from one part of organism to the other (for example, skin, bones, veins), and also transplantation of tissues between genetically identical twins (isotransplantation), because the tissue is perceived as "own".

§ At transplantation of non-vascular transplants (for example, corneas) the reaction of the immunological rejection fails to appear, because absence of circulation of blood in a transplant prevents the contact of immune cells with antigens, and for development of immune answer contact of antigen with the cells of the immune system is needed. § Transplantation of tissue between genetically heterogeneous people causes an immunological answer which can lead to rejection. The expressed reaction of rejection is increased along with growth of genetic distinctions between donor and recipient. Presently almost all organs are transplanted from people.

§ Transplantation of organs between genetically different members of the same kind is called allotransplantation. § Xenotransplantation is transplantation of organs between the individuals of different kinds (for example, the case of transplantation of heart of baboon to the child is known); such type of transplantation is accompanied a heavy immunological reaction and is not utillized practically.

Clinical types of rejection of transplant § There a few forms of rejection of transplant: from transient reaction, occuring in a few minutes after transplantation, to the slow reactions, showing up violation functions of the transplanted tissues over years after transplantation. Mechanisms, engaged in these different types of rejection, are also different. §

§ Acutest rejection: the acutest rejection is a quick as lightning reaction, occuring within the limits of a few minutes after transplantation and characterized by heavy necrotic vasculitis ischemic damage of displanted organ. The accumulation of immune complexes and activating of complement in the wall of the involved vessels can be determined by immunological methods. § The acutest rejection is being caused by presence in the blood of recipient of high levels of preexistent antibodies against antigens on the transplanted cells. The reaction of antibodies with antigens causes immunecomplex (the phenomenon of Arthus) damage in the vessels of transplant.

§ After the beginning of application of technique of direct determination of compatibility of tissues the acutest rejection became rare. § § Acute rejection: the acute rejection is observed often enough and can occur in from a few days to months after transplantation. It is sharp because even if the signs of rejection appear over the months after transplantation, it quickly makes progress from the moment of his beginning. The sharp rejection is characterized by necrosis of cells and violation of functions of organ (for example, sharp necrosis of myocardium and cardiac insufficiency in transplantation of heart). §

§ In the acute rejection both humoral and cellular mechanisms take part. Immune complexes are deposited in the shallow vessels of transplant and cause sharp vasculitis, leading to the ischemic changes. The cellular immune rejection is characterized by necrosis of parenchymatous cells and lymphocytal infiltration of tissues. § In transplantation of kidneys the acute rejection is seen as acute kidney insufficiency as a result of necrosis of kidney tubules with lymphocytal infiltration of interstitial tissue. For prevention and treatment of the sharp rejection immunosuppressive medications are used, for example, corticosteroids (prednisolon) and cyclosporins.

§ Chronic rejection: the chronic rejection is observed in most of the transplanted tissues and causes the progressive worsening of function of organ in months or years. Patients often have episodes of the sharp rejection, halted by therapy. § In chronic rejection cellular immunity (IV type of hypersensitiveness) is activated, that results in progressive elimination of parenchymatous cells. In the staggered tissue fibrosis develops with lymphocytal infiltration. Occasionally presence of chronic vasculitis proves the parallel influence of antibodies.

§ In treatment of the chronic rejection we try to attain balance between the damage of transplant and expressed toxic influencing of immunosuppressive medications which are usually utillized for prevention of rejection.

Acute rejection in transplantation of the heart

Acute rejection in transplantation of the heart

Autoimmunization and autoimmune diseases § Autoimmunization (autoallergy, autoaggression) is the state, characterized by appearance of reaction of the immune system on the normal antigens of patient's own tissues. § Autoimmunization is closely related to the concept of immunological tolerance (from Lat. tolerare). It is characterized by the state of areactivity ("tolerance") of lymphoid tissue in relation to antigens, able to cause immune answer.

§ In the period of ripening of lymphoid tissue there is immunological tolerance to the antigens of all organs and tissues, except for tissues of eye, thyroid, testicles, adrenal glands, cerebrum and nerves. It is considered that the antigens of these organs and tissues are bordered from lymphoid tissue by physiological barriers, which explains absence of tolerance of the immunocompetent system to them.

§ The immune system begins to recognize"own" and "alien" tissue antigens in new-born in a few weeks after birth. Thus the production of autoantibodies in small quantities constantly take a place on the extent of all life and autoantibodies, as supposed, take part in adjusting of different functions of organism. Their action is under control by Tsupressors and anti-idiotypic antibodies, that does not allow an autoimmune process to develop. § Autoimmunne diseases are diseases, in basis of which lies autoimmunity, that aggression of autoantibodies, circulatory immune complexes, containing autoantigens, and effector immune cells (killer lymphocytes) in regard to the antigens of own tissues of organism.

§ Therefore autoimmune diseases are also named autoaggressive. § Following the mechanism of autoimmunization, we distinguish two groups of autoimmune diseases. First group – organ-specific autoimmune diseases which develop in connection with the damage of physiological barriers of the immunologically isolated organs, that allows the immune system to react on their unchanged antigens by making of autoantibodies and sensibilized lymphocytes.

§ Thus morphological changes, typical mainly for DTH, develop in organs: tissue of organs is infiltrated by lymphocytes, parenchymatous elements perish, sclerosis develops in the end. This group includes thyreoiditis (disease of Khasimoto), encephalomyelitis, polyneuritis, dissipated sclerosis, idiopathic Addison's disease, aspermatogenia, sympathic ophthalmia. § Second group – organ-nonspecific autoimmune diseases. Leading to these diseases are violations of control of immunological homeostasis of the lymphoid system. Autoimmunization here develops in relation to the antigens of many organs and tissues, not possessing organ specificity and incapable to cause the products of antibodies at parenteral introduction.

§ Morphological changes, characteristic for the reactions of hypersensitiveness both slow and especially immediate types, develop in organs and tissues. This group of autoimmune diseases includes system lupus erythematosus, rheumatoid arthritis, system sclerodermia, dermatomyositis (group of rheumatic diseases), secondary thrombocytopenic purple (disease of Moshkovich). § There autoimmune diseases of intermediate type, which are close to diseases of the first or second type. These are myastenia gravis, diabetes mellitus of the I type, thyreotoxicosis, syndromes of Sjogren and Goodpasture and others.

§ Besides autoimmune diseases, there are diseases with autoimmune violations. Appearance of autoantigens at these diseases is connected to the change of antigen properties of tissues and organs – denaturation of tissue albumens (at a burn, irradiation, trauma, chronic inflammation, viral infection); formation of autoantigen is possible at influence of bacterial antigen, especially cross reactive (for example, at glomerulonephritis, rheumatism). § In formation of autoantigen a large value is given to gaptene mechanism, and both the products of metabolism and microorganisms, toxins and medications can play the role of gaptenes.

§ Autoimmunization in these terms determines not the origin of disease, but progress of typical for it local (organ) changes which reflect morphology of reactions of hypersensitivity of slow and immediate types. § This group of diseases includes: certain forms of glomerulonephritis, hepatitis, chronic gastritis and enteritis, cirrhosis of liver, burn disease, allergic anaemias, thrombocytopenia, agranulocytosis, medicinal allergy.

Immunodefitiency syndromes § Immunodefitiency syndromes are the extreme display of insufficiency of the immune system. They can be primary, conditioned by underdevelopment (hypoplasia, aplasia) of the immune system, which are inherited and innate immunodeficiency syndromes, or secondary (acquired), arising up in connection with illness or conducted treatment.

INNATE (PRIMARY) IMMUNODEFICIENCY § The morphological displays of primary insufficiency of immune answer are linked, as a rule, with the innate anomalies of thymus, or combination of these anomalies with underdevelopment of spleen and lymphatic nodes. § Heavy combined immunodeficiency - it one of the most heavy forms of innate immunodeficiency. It is characterized by the defection of stem lymphatic cells, that results in violation of development of both T-, and B-lymphocytes. The process of lowering of thymus from neck into mediastinum is disturbed. The amount of lymphocytes is sharply reduced in it.

§ There's also a few of them in lymphatic nodes, spleen, lymphoid tissue of intestine and peripheral blood. Immunoglobulines are absent in the serum. Insufficiency of both cellular and humoral immunity is reason of various heavy infectious (viral, mycotic, bacterial) diseases, arising up right after birth, that result in early death (usually on the first year of life). § Hypoplasia of thymus (syndrome of Di-George) is characterized by the lack of T-lymphocytesin blood, in thymus dependent areas of lymphatic nodes and spleen. The general amount of lymphocytes in peripheral blood is diminished. For patients the signs of insufficiency of cellular immunity are revealed, which manifests as heavy viral and mycotic infectious diseases in childhood.

§ Development of B-lymphocytes is usually not disturbed. Activity of T-helpers is almost absent, however concentration of immunoglobulins is usually normal. In thymus hypoplasia genetic defects are not exposed. This state is characterized also by absence of parathyroid glands, wrong development of arc of aorta and facial skull. In absence of parathyoid glands there is expressed hypocalcihemia, resulting in death in early age.

§ T-lymphopenia in the syndrome of Nezelof combines with violation of their function. It is assumed that it takes place as a result of violation of ripening of T-cells in thymus. The syndrome of Nezelof differs from syndrome of Di-George by the typical association of damaging of other structures, developing from the third and fourth gullet pockets. Parathyroid glands at this syndrome not damaged.

§ Thymus hypoplasia is successfully treated by the method of transplantation of human embryonic thymus, that restoring T-cell immunity. § Innate agammaglobulinemia (disease of Bruton) - genetically conditioned recession, related to the X chromosome, disease which is observed mainly in boys and characterized by violation of formation of Blymphocytes.

§ Pre-B cells (CD 10 positive) are found, but mature B-lymphocytes are absent in peripheral blood and in the B-zones of lymphatic nodes, tonsils and the spleen. Reactive follicles and plasmatic cells are absent in lymphatic nodes. Insufficiency of humoral immunity manifests in the noticeable diminishing or absence of immunoglobulins in serum. § Thymus and T-lymphocytes develop normally and cellular immunity is not violated. General amount of lymphocytes in peripheral blood is within the limits of norm, because an amount of T-cells which makes 80 -90% lymphocytes of blood usually is within the limits of norm.

§ Infectious diseases in a child develop usually in the second half of the first year of life since level of passively received maternal antibodies falls. Treatment of such patients is made by introduction of immunoglobulins. § The isolated deficiency of Ig. A is the most frequent immunodeficiency, found in one of 1000 people. It arises as result of defect of eventual differentiation of plasmatic cells, secreting Ig. A. For some patients this defect is related to abnornal function of Tsupressors. At most patients the deficiency of Ig. A runs asymptomatically.

§ Only a small quantity of patients has predisposition to the development of pulmonary and intestinal infections, because for them the lack of secretory Ig. A is determined in mucous membranes. At patients with the expressed deficiency of Ig. A antibodies are found in blood. These antibodies can react with Ig. A, which are in the transplanted blood, that results in development of hypersensitivity of the I type. § The immunodeficiency of various degree is found often enough. It arises as the secondary phenomenon in different diseases, or as a result of medicinal therapy and very rarely is primary disease.

§ Morphology of syndrome of the purchased immunodeficiency (AIDS) does not have a specific picture and differs on the different stages of its development. Changes are observed both in the central and in peripheral organs of immunogenesis (changes are most expressed in lymphatic nodes).

SECONDARY (ACQUIRED) IMMUNODEFICIENCY § Immunnodeficiency is always accompanied by development of opportunistic infections and on the final stage by development of malignant tumours, more frequent than all sarcomas of Kaposi and malignant B-cellular lymphomes. § The origin of infectious diseases depends on the type of immunodeficiency: § - the deficiency of T-cells predisposes to the infectious diseases, caused by viruses, mycobacteria, fungi and other intracellular microorganisms, like Pneumocystis carinii and Toxoplasma gondii.

§ - the deficiency of B-cells predisposes to the festering bacterial infectious diseases. §

§ These infectious diseases reflect relative importance of cellular and humoral answers in defence against different microbe agents. § Sarcoma of Kaposi and malignant B-cellular lymphomas are the most frequent malignant neoplasia which develop at patients with immunodeficiency. § The origin of malignant new formations can be connected to either violation of immune answer, directed on the removal of developing malignant cells, which appear in an organism (refuse of immune supervision) or due to immune stimulation of the damaged immune system in which the normal mechanism of control of cellular proliferation is broken (it results in the appearance of B-cellular lymphomas).

§ The lecture is over