Prof. MUDr. Milan Buc, milan.buc(at)fmed.uniba.sk
B lymphocytes are principal cells that mediate humoral adaptive immunity. After their maturation in the bone marrow, B cells enter peripheral lymphoid tissues, which are the sites of interaction with foreign antigens. Production of antibodies is initiated by the interaction of antigens with a small number of mature B cells specific for each antigen. An antigen binds to the membrane receptors on specific B cells and initiates a series of responses that lead to two principal changes: cell proliferation resulting in expansion of the clone, and differentiation to either plasma cells actively secreting antibodies or to memory cells.
Key words: B cells, subsets of B cells, memory B cells, plasma cells
A principal biological role of the immune system is an eradication of both external as well internal violators of integrity of the organism. External „enemies“ are represented mainly by germs; those of internal origin belong especially to potentially malignant cells that appear in our organisms as the results of a breakdown of their replication mechanisms.Under certain circumstances, however, the immune response can have deleterious effects, resulting in significant tissue damage or even death. This inappropriate immune response is termed hypersensitivity. Although the word hypersensitivity implies an increased response, the response is not always heightened but may, instead, be an inappropriate immune response to an antigen.
Several forms of hypersensitive reaction can be distinguished, reflecting differences in the effector molecules generated in the course of the reaction. In immediate hypersensitive reactions different antibody isotypes induce different immune effector molecules. IgE antibodies, for example, induce mast cell degranulation with release of histamine and other biologically active molecules. IgG and IgM antibodies, on the other hand, induce hypersensitive reactions by activating complement. The effector molecules in these reactions are the membrane-attack complex and such complement split products as C3a, C4a and C5a. In delayed-type hypersensitivity reactions, the effector molecules are various cytokines secreted by T helper cells and macrophages. As it became clear that different immune mechanisms can give rise to hypersensitive reactions, P. G. H. Gell and R. R. A. Coombs proposed a classification scheme in which hypersensitive reactions are divided into four types, I, II, III, and IV, each involving distinct mechanisms; later type V was added. Antibodies mediate four types of hypersensitive reactions: IgE-mediated (type I), cytotoxic (type II), immune complex (type III), and stimulatory/inhibitory (type V) hypersensitivity, respectively. T cells initiate the last type of hypersensitivity (type IV) and clinical symptoms appear more days after exposure; it is therefore referred to as delayed-type hypersensitivity (DTH). However, a great deal of com¬plexity exists within each type of reactions that blurs the boundaries between them.
The principal role of the immune system is to protect the organism from principally two the most dangerous events potentially threatening our life, i.e. infection and malignancy. However, sometimes the immune system instead of reacting against foreign and aberrant self-antigens can attack self-molecules. This inappropriate response of the immune system against self-components is termed autoimmunity.
There are 70 - 80 autoimmune disorders known till now and app. 5% of Caucasoid population suffers from them. Our understanding of autoimmunity has improved greatly during the last two decades, mainly because of the development of a variety of animal models of these diseases and the identification of genes that may predispose to autoimmunity. Nevertheless, the aetiology of most human autoimmune diseases remains still obscure.
The term “autoimmunity” is often erroneously used for a disease in which immune reactions accompany tissue injury; they are “a by-product” of a release of self-antigens to circulation without causing any damage; moreover, these “autoimmune reactions” help to degrade them and to remove them from the body.
A success of pregnancy depends on a proper implantation and induction of immune tolerance. The immune system secures it by various mechanisms – special cells, cytokines, HLA molecules, peripheral tolerance take part in.
The immune system of the newborn has also its own specifics as it matures relatively long time till it reaches the same protective ability as characteristic for adults.
The lecture deals with primary and secondary immunodefeciencies. It gives an overview on general clinical manifestations and their divisions according to the type of the immune functions defects. Must of the lecture devotes to AIDS.
Type I hypersensitivity belongs to the most common disorder mediated by immune reactions; it affects app. more than 30% of all individuals in Caucasoid population. Type I hypersensitivity is commonly called allergy. It is characterised by rapid onset (hence the term immediate hypersensitivity), within minutes of antigen challenge, and results in conspicuous clinical symptoms.
Cytokines are soluble peptides that induce activation, proliferation and differentiation of cells of the immune system. Moreover, cytokines influence functions of cells of other tissues and organs, esp. of nervous and endocrine systems. They act in very low concentrations (10-10 M) what makes them to be like hormones. However, hormones tend to be produced constitutively and are produced by endocrine organs. Cytokines, on the contrary, are secreted after activation of particular cells and secretion is short-lived, generally ranging from a few hours to a few days and there are no specialised organs for their synthesis. Cytokines influence target cell in 4 different ways, synergistic, antagonistic, pleiotropic, and redundant way, respectively. They ca act in a autocrine, paracrine and endocrine manner. There are many cytokines that can be divided into those regulating innate and adaptive immunity, to the group of cytokines endowed by chemotactic properties and those supporting growth of hematopoietic and immune system cells.
Histocompatibility molecules are genetically determined proteins present in membranes of all nucleated cells. They form a unique system for which the term “Major Histocompatibility Complex (MHC)” was coined. Each vertebrate species is characterised by its own MHC; that of humans has an abbreviation HLA. This acronym is derived from the words: “human leucocyte antigens” as its fist molecules were discovered in membranes of leucocytes.
Protein antigens are no able to induce an immune response without being previously processed by antigen presenting cells (APCs). Following their processing that comprises their splitting to smaller fragments – peptides, APs subsequently present them to T cells; moreover, they activate them and polarise to a specific biological functions. Depending of antigen origin, there are two presentation pathways, exogenous and endogenous. Antigens originated from outside of APC, e.g. bacterial toxins, enzymes, etc., are presented by exogenous pathway and presented molecules are class II HLA molecules. T cell, that recognise presented peptides belong to helper subset of T cells. Antigens originated in the cytosol, such as antigens that appear in the cytoplasm of virus infected cells, are presented by endogenous pathway and presented molecules belong to class I HL-A molecules. T cells, that recognise presented peptides, represent cytotoxic T cells.
Phagocytosis is a process of bacteria engulfment and their killing. The phagocytic cells of mammals belong to two complementary systems, the myeloid and mononuclear-phagocytic systems. The myeloid system consists of cells that phagocyte rapidly, however they are not able of sustained effort. Tthey are represented by neutrophils and eosinophils. In contrast, cells of the mononuclear-phagocytic system act more slowly but are capable of repeated phagocytosis. Mmonocytes and macrophages are principal cell responsible for. Process of phagocytosis can be divided into several steps: chemotactic movement of phagocytes towards invading bacteria, opsonisation and recognition of bacteria by specific receptors, their engulfment and phagolysosome formation, bacteria killing and resolution. Bacteria can be killed by oxygen or nitrogen dependent mechanisms and by various antibacterial substances.