N Failure to thrive, sudden death, often in first week, some. 4 year survivors. 2. Autosomal recessive lymphopenia. (Nezelof Syndrome) late absent infan- tonsils.
What's New In Immunol ogy?W D. ARMSTRONG, MD SUMMARY Since 1950, immunology has developed with such rapidity as an interdisciplinary science that even those within the field have difficulty keeping adequately informed. For this reason it is important that those who are closer to the subject, wherever possible, apply recent advances to the practice of medicine in general and primary care in particular. This paper describes a limited number of recent advances in the field of cellular immunology and immunodeficiency diseases. Above all, it attempts to relate the practical significance of these discoveries to the care of the patient by the primary care physician. Dr. Armstrong is associate clinical professor of pathology at the University of Alberta in Edmonton. Lin, Cooper and Wortis of the Sloan Kettering Cancer Center and Rockefeller University. The villous processes depicted in these drawings are believed responsible for the cell contact of T and B cells, as well as erythrocyte attachment in the erythrocyte rosette formation. Stimulation of the T and B cells by antigen is a complex process of antigen preparation by macrophages and recognition by receptors on the surface of antigen-reactive cells. The latter cells will respond only to those antigens for T and B Cell Interaction - A Model Immunologists agree that there are three basic cell types which they were genetically programmed during fetal life, as postulated by the clonal selection hypothesis of Burnet. in the immune response. Theoretically one could argue that there are an estimated 1. The stem cell resides in the bone marrow and is 100,000 clones or families of cells, each of which responds mother to the lymphoid cells which go to the thymus to a different antigen. In this way only a limited number of gland, (the primary lymphoid organ) or the spleen and lymph nodes (secondary lymphoid organs).
THE RAPIDLY expanding forefront of immunological research has produced a model of thymus (T) and bone marrow (B) derived cell interaction to explain immune responsiveness. This model is used as a basis for categorizing immunodeficiency diseases. Thus, immunodeficiency has been divided into three main groups: T, B and T-B cell deficiencies.
2. Thymus derived or T cells are subsequently produced in the thymus and passed into the blood, thence to the Fig. 1. lymph nodes. 3. Bone marrow or bursa-derived B cells come directly from the marrow to the secondary lymphoid organs, bypassing the thymus. Since the discovery that the bursa of Fabricius in the cloaca of the chicken has an important role in the maturation of B cells in chickens, scientists have speculated that in man, lymphoid aggregations such as the appendix, Peyer's patches and tonsils serve a similar role as bursa equivalents. This is a controversial area and convincing evidence is not yet available. T and B cells can be visualized with the scanning electron microscope. Figure 1 illustrates the difference in the cell membrane or surface architecture as detected by CANADIAN FAMILY PHYSICIAN/FEBRUARY, 1975
Figure 1. A model of T-B cell interaction in response to antigen. 'Helper' factor, believed to be produced by the T-cell, may be modulated by the macrophage. T-independent antigens do not require the helper factor or T-cell contact to produce blastogenesis and antibody. 69
the body's immunocytes will respond to a given antigen, preserving the other antigen-reactive cells for the appropriate antigens, as they are encountered by the body. Many antigens are capable of triggering antigen-reactive B cells directly. Recent evidence suggests that the amount and form of the antigen determine whether the thymus is necessary at all. Once stimulated, these cells form blast cells (blastogenesis) which stain with pyronin green by virtue of their increased RNA content. These large pyroninophilic blast cells in turn divide and differentiate, ultimately into antibody producing plasma cells and long lived lymphocytes which are believed responsible for immunologic memory. Dr. Erwin Diener and his colleagues of the Transplantation Immunology Unit in Edmonton have been working on the B cell response and have been able to trace the progress of surface stimulation of immunocytes by radioactively labelled antigen. They have demonstrated that after antigen stimulation in vitro, antigen accumulates on the aggregated surface receptor sites of the cell after which blastogenesis commences. Dr. Diener has shown that if the antigen aggregations can be cross-linked to a critical level on the cell surface, the affected cell can be made to switch off (immunologic tolerance) rather than on to immunity. If this process could be established in man for a group of antigens, such as the transplantation antigens, this would constitute a major breakthrough in the area of transplantation. On the other hand, those antigens which are not adequately able to stimulate B cells directly (thymus dependent antigens) may be processed by macrophages which then submit the antigen to T cells (Fig. 2). A 'helper factor' is then produced by the stimulated T cells. This factor, modulated by macrophages, is believed to contact B
cells which then respond and produce antibody, as in the case of thymus independent antigens. Recent evidence indicates that the thymus system amplifies the immune response to thymus dependent antigens. This permits the body to respond maximally to small amounts of these antigens, which in the case of certain infections would be a life saving event. There is an alternate pathway in which the thymus dependent antigen also stimulates the T cell to enter blastogenesis, divide and differentiate into 'killer cell' lymphocytes. These cells are most notable for their ability to participate in graft rejection and delayed type hypersensitivity by virtue of direct cell contact with the antigen. Some byproducts of this process are called lymphokines. The two most notable lymphokines are: migratory inhibitory factor (MIF), which causes macrophages to aggregate in the area of the antigen and is useful as a laboratory indicator of all cell mediated immunity and transfer factor (TF) which is useful in the treatment of some immune deficiency diseases discussed below. This model of T-B cell interaction permits immunologists to dissect the various components of the immune response in an effort to handle the problems of graft rejection and immune deficiency disease. It also provides a key to unlock the mysteries of immune deficiency diseases. These diseases may be divided into those dependent on T and/or B cell deficiencies plus deficiencies of phagocytosis.
Immune Deficiency Diseases Although there are more than 50 immune deficiency diseases, their overall incidence is less than one percent of the total population. Children account for 58 percent of the cases. Under age 15, 83 percent of patients are male; over 15 years, 60 percent are female.
General Clinical Findings Fig. 2 STEM CELL
T- INDEPENDENT
ANTIGEN
EEN
_7
The major symptoms are increased susceptibility, frequency, severity, duration and complications of infection, often with organisms of low pathogenicity. The clinical findings usually include recurrent respiratory infections, severe bacterial infections (e.g. pneumonia, sepsis and meningitis), recurrent diarrhea and failure to thrive. Often these findings are complicated further by draining ears, pallor and irritability, pyoderma, chronic conjunctivitis, malabsorption and decreased lymph node and tonsil size.
B Cell Immunodeficiency Disease: dn
\
/
FACTORS eg. M.1 F
TF
LARGE PYRONINOPHILIC BLAST CELL
etc. / \
A /A AA
