Ontogenetic development

1. In mature mammals, the primary lymphoid organs are the thymus and bone marrow. During fetal development the liver is one of the primary organs of lymphoid development. In early fetal development, lymphocyte precursors are derived from the fetal yolk sac. By the fourth or fifth week of gestation, lymphocytes originate from the liver and thereafter from the bone marrow. In the bone marrow, pluripotent stem cells differentiate into lymphocytes, granulocytes, monocytes, erythrocytes, and megakaryocytes.

B cells undergo early growth in the bone marrow and finally emerge with membrane-bound surface IgM or both IgM and IgD, although they have not yet encountered antigen. This growth that takes place in the bone marrow is antigen-independent B-lymphocyte maturation. B cells also proliferate in response to antigen-dependent signals and eventually differentiate into antibody-secreting cells or plasma cells. This proliferation is dependent on antigen binding to the B-cell receptor. This receptor comprises membrane-bound immunoglobulin and two additional chains required for its stable expression, Ig-a and Ig-b. There are two such heterodimers that flank the membrane-bound immunoglobulin and help to mediate signal transduction. B-cell activation also requires costimulation in the form of T cell help in two ways. The first is stimulation with IL-4, produced by the CD4+ T cell, which is an important B-cell growth factor. The second is T- and B-cell interaction via the molecules CD40 and CD40L (CD154); CD40 is expressed on the B cell, and CD40L is found on CD4 T cells. The interaction of these molecules facilitates class switching to IgA, IgG, and IgE. In a rare clinical immunodeficiency state, patients with X-linked hyper-IgM syndrome lack CD40L and are unable to produce antibodies of the IgA, IgG, and IgE classes. B cells also possess a cell surface molecule, B7 (CD80), which is up-regulated after ligation of CD40. B7 is a counterreceptor for CD28, a costimulatory molecule expressed on T cells. This costimulatory molecular interaction optimizes cytokine secretion and the T–B cell interaction. A human fetus is capable of synthesizing IgM antibody by 10.5 weeks of gestation, IgG by 12 weeks, and IgA antibody by 30 weeks. The immunocompetent human infant, typically born without antigen stimulation (unless infected in utero), has little circulating IgA and IgM. IgG antibody in the newborn is almost completely derived from the mother by active and selective transport across the placenta. Adult serum levels of IgG, IgM, and IgA are attained at different developmental stages.

From 6 to 8 weeks of gestation, T-lymphocyte precursors migrate through the thymus, which is derived from the third and fourth embryonic pharyngeal pouches and is located in the mediastinum. The thymus functions to produce T lymphocytes and is the site of initiation of T-lymphocyte differentiation. A large number of T cells migrate to the thymus and become fully immunocompetent T cells. In addition, a number of T cells that are autoreactive die in the thymus. Under the influence of various cytokines (such as thymosin), T cells in the thymus undergo growth and differentiation and deletion of autoreactive clones. Functional development of cellular responses progressively matures as the fetus develops through parturition and infancy into adulthood.

2. Phagocytic cells are seen in the human fetus at 2 months of gestation as a few myelocytes and histiocytes present in the early yolk sac stage of hematopoiesis. Monocytes first appear in the spleen and lymph nodes at 4 to 5 months of gestation, with gradual maturation of macrophage function with advanced fetal age. The spleen, lymph nodes, and gut-associated lymphoid tissue are considered secondary lymphoid organs. Lymph nodes are peripherally dispersed throughout the body and function to localize the spread of infection. Lymph nodes are arranged in a reticular pattern with a cortex and medulla. B-lymphocytes are found in the cortex (follicles and germinal centers) as well as in the medulla, whereas T lymphocytes are primarily found in the medullary and cortical areas of the lymph nodes (see Fig. 1.2). The spleen is also divided into T- and B-cell areas similar to that of the lymph node. The spleen functions primarily to filter and process antigens from the blood.

3. Complement components are synthesized by the fetus early in gestation, either at the same time as or just before the beginning of immunoglobulin synthesis. There is almost no placental transfer of complement components C1q, C2, C4, C3, and C5, and the total hemolytic complement in the newborn is low. Such deficiency and dysfunction may be responsible for the relative opsonic deficiency in newborns. Complement plays a very important role in both innate and adaptive immunity. In the humoral immune response, complement opsonizes antigen as well as immune complexes for uptake by the complement receptor type 2 (CR2, CD21), is a coreceptor for B-cell activation, and is expressed primarily on B cells, follicular dendritic cells (FDC), and some T cells. Many different mechanisms are responsible for the complement-mediated promotion of the humoral immune response. These include:

a. Enhancing antigen uptake and processing by both antigen-specific and nonspecific B cells for presentation to specific T cells.

b. Activating a CD21/CD19 complex-mediated signaling pathway in B cells (this stimulus is synergistic to that induced by antigen interaction with the B-cell receptor).

c. Promoting the interaction between B cells and follicular dendritic cells, in which C3d-bearing immune complexes participate in intracellular bridging. C3d is the ligand for CR2 on B cells, and is instrumental in B cell activation.

CR2 can play a role in the development of autoimmune disease by determining B cell tolerance toward self-antigens. CR2 may be a key factor in the observed correlation between autoimmune disease and deficiency of the early complement components.