Raymond D. A. Peterson

The pathogenesis of immunologic deficiency diseases

Abstract Several clinically distinct types of immunologic deficiency syndromes have been considered, together with recent advances in our knowledge of the evolution and development of the immune system. Integration of clinical and experimental observations has permitted a reasonable definition of the pathogenesis of several clinical types of agammaglobulinemia. Hopefully, these observations will direct further studies of the development and maintenance of the immune system in man. Clinical and experimental studies are also presented to emphasize the relationship between immunogenesis and leukemogenesis.

Lymphoid tissue abnormalities associated with ataxia-telangiectasia

Abstract Systematic morphologic and functional studies of the immune system were undertaken in eight patients with ataxia-telangiectasia. Seven of the eight had siblings with the disease. Three died, one apparently of pneumonia, one of pneumococcal meningitis and one of small cell lymphosarcoma. No thymus was found at autopsy in one; in another, the thymus was small, lacking in Hassalls corpuscles and embryonic in appearance. Two thymus biopsy specimens in other patients had this same histologic abnormality. Lymph nodes were normal in two instances, abnormal in six; and tonsillar tissue was deficient in follicle formation in all four patients in whom biopsy was performed. As a group, these patients tended to have hematologic abnormalities involving elements other than lymphoid cells; but these were quite variable, both in the cell lines involved and the degree of deficit or hyperplasia. All the patients had an immunologic deficit, observed most consistently in the response to skin homografts and antigens ordinarily provocative of delayed allergic responses. The circulating antibody response to certain antigens was also deficient in most of the children. These additional data on our patient group, and those from other published reports, emphasize the association of this neurologic and vascular disease with defective thymic development, generalized lymphoreticular abnormalities, immunologic deficiency (particularly of cellular immunity), and unusual susceptibility to lymphoreticular malignancy.

Reduced antibody forming capacity during the incubation period of passage a leukemia in c3h mice.

Summary Injection of Grosss passage A leukemia virus in newborn C3Hf/Bi mice interferes with the development of their responsiveness to bacteriophage T2. This deficiency was present in mice antigenically stimulated at 3 weeks and 9 weeks of age, and, notably, before obvious malignant cells are present.

A DEFECT IN CELLULAR IMMUNITY DURING THE INCUBATION PERIOD OF PASSAGE A LEUKEMIA IN C3H MICE.

Summary Six-week-old C3H mice injected neonatally with Gross passage A leukemia virus were found to be unable to reject skin grafts across a weak histocompatibility barrier. The similarity of the defects in the immune mechanisms of these mice to those of the neonatally thymectomized mice suggests that the establishment of the oncogenic agent in the neonatal thymus results in marked functional impairment long before histologic changes are apparent.

Wheal and erythema allergy in patients with agammaglobulinemia.

Abstract Atopic diseases have been reported in patients with low gamma globulin levels, associated with demonstrable skin-sensitizing antibodies in some cases. One patient is reported here who lost previous wheal and erythema sensitivity when she developed a severe hypogammaglobulinemia. Typical atopic dermatitis occurred in 4 of 23 boys with congenital, sex-linked, recessive agammaglobulinemia. No wheal and erythema allergy was demontrable in any of these patients. Attempts to induce the development of skin-sensitizing antibodies to an Ascaris extract in 6 congenital agammaglobulinemic patients were uniformly unsuccessful. These patients did, however, all develop delayed sensitivity to the Ascaris.

Endotoxin activity of a house dust extract

Abstract A commercial dust extract has been demonstrated to contain endotoxin-like activity. The clinical significance of this finding is unclear, but any substance as biologically active as endotoxin must be seriously considered to have some action when it is injected into a living organism. Any study of the action of dust extract in clinical allergy must consider this potent substance.

THE ROLE OF THE THYMUS IN IMMUNE PROCESS

Historically, the thymus has been an enigma, so in many ways has the larger complex, the lymphoid system of tissues and cells. However, during these last four or five years, we have taken a “new look” not only a t the thymus, theretofore an organ of unknown function, but a t the appendix and, even more recently, a t the tonsils, which are also tissues usually considered readily dispensable. The thymus clearly functions as a “source” tissue in the ontogenesis of cell systems intimately concerned with adaptive immunity. The appendix apparently has a similar function in the rabbit and perhaps in other mammals. Recent evidence has suggested that the tonsils may be associated with the development of capacity for plasma cell formation and immunoglobulin synthesis in the young animal. A new concept of the lymphoid system is emerging gradually, and i t is with this developing concept that we would Like to deal. I t may be useful a t the outset to sketch what we see as the broad outlines of the lymphoid system a t the beginning of 1965: a “still picture” of a rapidly changing complex of relationships. At present, then, we see a two-way division in the lymphoid system. The oldest, a distinction implicit in experimental observations going back to the 1890’s, and perhaps earlier, is that of “central lymphoid tissue” and “peripheral lymphoid tissue” (Beard, 1894, 1900; Hammar, 1921). The prototype of central lymphoid tissue is the thymus: a tissue originating from the epithelium of the gut, exercising a major function in the maturation of adaptive immunity largely through its influence on the peripheral lymphoid tissues, but remaining relatively inactive in dayto-day immunologic function (Bjfirneboe & Gormsen, 1943; Fagraeus, 1948; Miller, 1962a; Good et al., 1 9 6 2 ~ ) . Other tissues of this type are the burs5 of Fabricius, a cloaca1 lymphoid organ of birds, and the appendix of the rabbit. All three of these organs have been shown experimentally to play a role in the maturation of antibody producing capacity (Glick et al., 1956; Mueller et al., 1960, Archer & Pierce, 1961; Miller, 196%; Archer et al., 1 9 6 3 ~ ; Sutherland et al., 1 9 6 4 ~ ) .

Ontogenetic Development of the Germinal Centers and Their Function — Relationship to the Bursa of Fabricius

In this presentation we shall briefly review the evidence which suggests that the lymphoid cells of germinal centers in chickens are direct descendants of lymphoid cells of the bursa of Fabricius; these cells appear to represent intermediate stages in plasma cell differentiation. Further, we shall present evidence that Peyer’s patch type of intestinal lymphoid tissues serve as the mammalian counterpart of the avian bursa.

THE THYMUS IN IMMUNOBIOLOGY: WITH SPECIAL REFERENCE TO AUTOIMMUNE DISEASE*

The thymus has become a subject of intense interest and activity in biology and in clinical medicine in recent years.’ However, interest in the thymus is not only of recent origin. Indeed, many outstanding investigations were carried out on this organ before the turn of the century. Viewed in the perspective of our current knowledge, some of the earlier investigations were most incisive and contributory. Perhaps, unfortunately, these observations captured the imagination of certain clinicians and the concept of status thymicolymphaticus evolved. In retrospect, it would seem that this concept, erroneous in substance, set back investigations on the thymus. Thus, for a period, studies of the thymus seem to have fallen into disrepute. During the thirties and forties few significant contributions were made. Consequently, we feel it is entirely appropriate that a t least some of the energies for the current surge of study, investigations and enthusiasm for the thymus should have derived from the clinic.’ ” The authors hope in this publication to show tha t already the intensive laboratory effort is having a positive feedback to the clinic and already may be making contributions to our understanding of clinical disease. Our interest in the thymus in Minneapolis developed in 1953 when Good and Varco‘.’ had the opportunity to investigate an unusual person, a man who had severe deficiency of his immunological reactions and lacked gamma globulin. He had apparently developed this deficiency during adult life and could be defined as one of the patients with “acquired agammaglobulinemia.” An interesting aspect of this patient was that he also suffered from rheumatoid arthritis of a moderately severe type. He had developed this combination of diseases in apparent temporal association with the development of a huge tumor in the anterior chest. This huge mass in the mediastinum turned out to be a benign thymoma which was composed almost entirely of epithelial and stromal cells. I t seemed to us unusual that two such rare diseases as benign

Ataxia–Telangiectasia: An Important Clue

The paper by Carbonari et al. in this issue of the Journal calls attention to the rapidly expanding knowledge of the molecular processes underlying ataxia—telangiectasia.1 Previous observations pro...