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  2. 2. INTRODUCTION B cells are lymphocytes that play a large role in the humoral immune response ( as opposed to the cell- mediated immune response, which is governed by T cells). The principal functions of B cells are to make antibodies against antigens, perform the role of Antigen Presenting Cells ( APCs) and eventually develop into memory B cells after activation by antigen interaction. B cells are an essential component of the adaptive immune system The abbreviation " B", in B cell, comes from the bursa of Fabricius in birds, where they mature. In mammals, immature B cells are formed in the bone marrow.
  3. 3. Functions The human body makes millions of different types of B cells each day that circulate in the blood and lymphatic system performing the role of immune surveillance. They do not produce antibodies until they become fully activated. Each B cell has a unique receptor protein ( referred to as the B cell receptor ( BCR)) on its surface that will bind to one particular antigen. The BCR is a membrane- bound immunoglobulin, and it is this molecule that allows the distinction of B cells from other types of lymphocyte, as well as being the main protein involved in B cell activation. Once a B cell encounters its cognate antigen and receives an additional signal from a T helper cell, it can further differentiate into one of the two types of B cells listed below ( plasma B cells and memory B cells). The B cell may either become one of these cell types directly or it may undergo an intermediate differentiation step, the germinal center reaction, where the B cell will hypermutate the variable region of its immunoglobulin gene (" somatic hypermutation") and possibly undergo class switching. Activation of B cells B cell recognition of antigen is not the only element necessary for B cell activation ( a combination of clonal proliferation and terminal
  4. 4. differentiation into plasma cells). B cells that have not been exposed to antigen, also known as naïve B cells, can be activated in a T cell- dependent or - independent manner. T cell- dependent activation Once a pathogen is ingested by an antigen- presenting cell such as a macrophage or dendritic cell, the pathogen' s proteins are then digested to peptides and attached to a class II MHC protein. This complex is then moved to the outside of the cell membrane. The macrophage is now activated to deliver multiple signals to a specific T cell that recognizes the peptide presented. The T cell is then stimulated to produce autocrines ( Refer to Autocrine signalling), resulting in the proliferation and differentiation to effector and memory T cells. Helper T cells ( i. e CD4+ T cells) then activate specific B cells through a phenomenon known as an Immunological synapse. Activated B cells subsequently produce antibodies which assist in inhibiting pathogens until phagocytes ( i. e macrophages, neutrophils) or the complement system for example clears the host of the pathogen( s). Most antigens are T- dependent, meaning T cell help is required for maximal antibody production. With a T- dependent antigen, the first signal comes from antigen cross linking the B cell receptor ( BCR) and the second signal comes from co- stimulation provided by a T cell. T dependent antigens contain proteins that are presented on B cell Class II MHC to a special subtype of T cell called a Th2 cell.
  5. 5. When a B cell processes and presents the same antigen to the primed Th cell, the T cell secretes cytokines that activate the B cell. These cytokines trigger B cell proliferation and differentiation into plasma cells. Isotype switching to IgG, IgA, and IgE and memory cell generation occur in response to T- dependent antigens. This isotype switching is known as Class Switch Recombination ( CSR). Once this switch has occurred that particular B cell will usually no longer make the earlier isotypes, IgM or IgD. T cell- independent activation Many antigens are T cell- independent in that they can deliver both of the signals to the B cell. Mice without a thymus ( nude or athymic mice that do not produce any T cells) can respond to T independent antigens. Many bacteria have repeating carbohydrate epitopes that stimulate B cells, by cross- linking the IgM antigen receptors in the B cell, responding with IgM synthesis in the absence of T cell help. There are two types of T cell independent activation; Type 1 T cell- independent ( polyclonal) activation, and type 2 T cell- independent activation ( in which macrophages present several of the same antigen in a way that causes cross- linking of antibodies on the surface of B cells).
  6. 6. B cell immunodeficiencies B cell immunodeficiencies are antibody deficiency disorders that are restricted to antibody function. Either B lymphocyte development is impaired, or B cells fail to respond to T cell signals. All or only selected subsets of immunoglobulins may be deficient. Patients have recurrent pyogenic infections with encapsulated bacteria. Infections require early and vigorous treatment with antibiotics and life- long immunoglobulin replacement therapy. 1. X- linked agammaglobulinemia ( XLA) 2. Hyper- IgM syndrome ( HIM) 3. IgA deficiency 4 Common variable immunodeficiency ( CVID) 5 Other B cell deficiencies X- linked agammaglobulinemia ( XLA) X- linked agammaglobulinemia ( XLA) is a typical antibody deficiency in which production of antibodies is prevented due to a block in B cell maturation. Serum concentrations of IgG, IgA, and IgM are markedly reduced. Levels of circulating B cells are significantly decreased and plasma cells are absent from lymph nodes and bone
  7. 7. marrow, although the number of T cells is normal or even increased. The clinical phenotype may be variable and even members of the same family can have different symptoms. The majority of affected boys present with recurrent bacterial infections from the age of 4 to 12 months following the disappearance of maternal immunoglobulin. Infections caused by pyogenic bacteria are the most common clinical manifestations. Rare cases of XLA in adults. Hyper- IgM Syndrome Hyper- IgM syndrome ( HIM) represents a group of distinct entities characterized by defective normal or elevated IgM in the presence of diminished IgG and IgA levels. Seventy per cent of the cases are X- linked in inheritance, and others are autosomal recessive. Male patients with X- linked hyper- IgM have a history of recurrent pyogenic infections, and are particularly susceptible to Pneumocystis
  8. 8. carinii. They are also prone to profound neutropenia, autoimmune hemolytic anemia, and thrombocytopenic purpura. Liver disease including sclerosing holangitis, viral hepatitis as well as hepatic lymphoma are common and their frequencies increase with age. The long- term survival rate for patients with XHIM is poor despite regular use of intravenous immunoglobulins. Less than 30% of the patients are alive at 25 years of age. Major causes of death include Pneumocystis carinii pneumonia early in life, liver disease, and malignancies in later life. Allogeneic bone marrow transplantation or non- myeloablative bone marrow transplantation from matched, unrelated donors have been successful in the treatment of hyper- IgM syndrome. IgA Deficiency Selective IgA deficiency is the most common form of immunodeficiency in the Western world, affecting approximately 1 in 600 individuals. Only about one third of the patients are
  9. 9. particularly prone to infections. Most patients have IgA levels below 5 mg/ dl. The serum concentrations of the other immunoglobulins are usually normal, but patients have a high incidence of autoantibodies, many with allergies including food reactions, allergic conjunctivitis, rhinitis, urticaria, atopic eczema, and bronchial asthma. In about two thirds of the cases, the deficiency does not lead to an increased occurrence of infections, whereas the remaining patients suffer from bacterial infections in both the upper and lower respiratory tract. Common variable immunodeficiency ( CVID) Common variable immunodeficiency ( CVID) is a group of undifferentiated disorders with defective antibody formation. The incidence is approximately 1:25,000. Patients with CVID usually have normal number of circulating B cells, but low serum levels of IgG and IgA. However, the B cells are defective. CVID affects both females and males equally and it usually has later age of onset than other antigen IDs. Patients have an unusually high incidence of lymphoreticular and gastrointestinal malignancies and the incidence
  10. 10. of autoimmune disorders is also increased. CVID forms arise from several different genetic defects. Other B cell deficiencie Other B cell deficiencies have been described including, for example μ heavy chain deficiency; λ 5 surrogate light chain deficiency; and κ light chain deficiency.