In 1925, Murphy and Sturm1 at Rockefeller Institute, New York, demonstrated that immunized rabbits, x-rayed in doses sufficient to reduce the amount of lymphoid tissue without damaging bone marrow, showed a deficiency in production of precipitins, bacterial agglutinins, and protective antibodies. Conversely, rabbits subjected to dry heat sufficient to increase activity of lymphoid organs developed antibodies in larger quantities than control nonimmunized rabbits. Their findings, however, had little if any influence on the longstanding concept of the reticuloendothelial system as the cellular source of antibodies. The first indication to the contrary, suggesting a role for the lymphoid system, was provided by McMaster2 (1891-1973), also at Rockefeller Institute, who demonstrated the early appearance of specific antimicrobial antibodies to corresponding antigens only in regional cervical lymph nodes homolateral to intradermally injected mouse ears; later identification of antibodies in contralateral nodes was attributed to systemic circulation.
Convincing evidence that lymphocytes were instrumental in the production of antibodies was next provided by University of Pennsylvania pathologist Ehrich (1900-1967) and pediatrician Harris (1912- ) in 1942. Their immunologic studies identified specific antibodies in the efferent fluid of popliteal lymph nodes within days after injecting rabbit hind food pads with either typhoid antigen or sheep erythrocytes.3 Subsequently, they extended their findings, clearly demonstrating that the lymphocytes within these nodes produced, rather than absorbed, the antibodies contained in the fluid.4 Uncovering the association of lymphocytes and antibody formation initiated the flow of investigations elucidating differentiation of thymus-derived (T-cell) and bone marrow–derived (B-cell) lymphocytes and their respective roles in different types of immune functions and reactions. Brief summaries of reports of selected early studies, particularly centered on the B lymphocyte, are found on the following pages (843, 865, 871, 888 and 895) of this thematic issue.
Sheldon G. Cohen, MD, Scientific Advisor
Bernard W. Janicki, PhD, Emeritus Science Administrator Joy C. Mazzullo, BA, Research/Editorial Associate
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, Md
1. Murphy JB, Sturm E. A comparison of the effects of x-ray and dry heat on antibody formation. J Exp Med 1925;41:245-55. 2. McMaster PD, Hudach SS. The formation of agglutinins within lymph nodes. J Exp Med 1935;61:785-804.
3. Ehrich WE, Harris TN. The formation of antibodies in the popliteal lymph node in rabbits. J Exp Med 1942;76:335-48. 4. Harris TN, Grimm E, Mertens E, Ehrich WE. The role of the lymphocyte in antibody formation. J Exp Med 1945;81:73-83.
Images
Philip D. McMaster, MD (courtesy of the Rockefeller Archives Center); William E. Ehrich, MD (courtesy of the University of Pennsylvania School of Medicine Archives); Tzvee N. Harris, MD (courtesy of the College of Physicians of Philadelphia, Historical Medical Library).
The chicken having both bursa and thymus led to suggestions that both lymphoid organs may possess distinct immune functions. Cooper (1933- ) at the University of Minnesota in 1966 provided a cornerstone for immunology. In extending Glick’s and Miller’s observa-tions, he demonstrated that bursa and thymus form a component system of immunologically functional lymphocytes. Thymectomized chicks with intact bursas retarded immunologic graft rejection without ablating antibody production; combined bursectomy and thymec-tomy immediately posthatching followed by sublethal irradiation led to a total loss of immune function. The conclusion was that bursa-dependent lymphocytes give rise to larger cells of germinal lymphocyte centers and to plasma cells that produce antibodies, and thymus-dependent cells form circulating small lymphocyte populations responsible for immunologic skin graft rejection.1
Immune deficiency in chicks lacking functional bursal derived lymphocytes suggested to Cooper similarities to what might be a human disease counterpart, agammaglobulinemia immunodeficiency. The syndrome of absent gamma globulins and defective antibody production successfully treated by reconstitution with serum gamma globulin, had been described by Bruton at Walter Reed Army Hospital Pediatrics Department fourteen years previously.2
1. Cooper MD, Peterson RA, South MA, Good RA. The functions of the thymus system and the bursa system in the chicken. J Exp Med 1966;123:75-102.
2. Bruton OC. Agammamlobulinemia. Pediatrics 1952;9:722-8. Images
Max D. Cooper, MD (courtesy of the National Library of Medicine).
Col Ogden C. Bruton, MC, USA, MD (courtesy of Walter Reed Army Medical Center Archives).
Shortly after documentation of his 4-year study and management of the first reported immunodeficiency disease, Bruton of Walter Reed Army Medical Center was joined by Janeway and his Boston Children’s Hospital and Harvard Medical School associates in introducing agammaglobulinemia at a session of the Society for Pediatric Research in May 1952.1 Their presentation described collective observations of 3 patients, all boys, age 9 years. The syndrome was characterized by the commonality of multiple, recurrent, severe, septic bacterial infections; deficient antibody production to infecting microorganisms and vaccine immunizations; extremely low levels of serum gamma globulins despite normal serum total proteins; and successful treatment with injections of donor immune gamma globulin. By the next year, Janeway had 9 additional case studies with identical features to report.2
Analysis of data of further investigations confirmed Cooper’s hypothesized counterpart association of a bursectomized animal model and Bruton’s agammaglobulinemia immuno-deficiency. The correlation of the absence of antibodies and lack of plasma cells or fully developed B cells reflected X-linked genetic transmission of B-cell–line pathogenesis. Concurrent resistance to viral infection and delayed hypersensitivity responses indicated an unimpaired parallel T-cell arm.
1. Bruton OC, Apt L, Gatlin D, Janeway CA. Absence of serum gamma globulins. AMA. Am J Dis Child 1952; 84: 632-36.
2. Janeway CA, Apt L, Gitlin D. Agammaglobulinemia. Trans Assoc Am Physician 1953; 66: 200-02.
Images
Col Ogden C. Bruton, MC, USA, MD (courtesy of Walter Reed Army Medical Center Archives).
Charles A. Janeway, MD (reproduced from Geha RS, Janeway CA, Rosen FS. The discov-ery of gamma globulin therapy and primary immunodeficiency diseases at Boston Children’s Hospital. J Allergy Clin Immunol 2005;116:937-40.)
The development of insights, technologies, and manipulation of T-cell and B-cell experimental models led to clinical designs aimed at correcting life-threatening immunodeficiency disorders. In 1968, inventive procedures to effect successful cellular competence were reported independently by 2 pioneering groups.
Good (1922-2002) and his team at University of Minnesota undertook treatment of a sex-linked lymphopenic patient with immunodeficiency lacking both T and B cells. Administered donor peripheral buffy coat and bone marrow cells from a histocompatible, immunocompetent sister induced a mild graft-versus-host reaction. On recovery, the recipient was found to be fully immunocompetent and chimeric by karyotyping and donor blood type.1
Bach2 (1934- ) at the University of Wisconsin treated a 2-year-old boy affected by Wiskott-Aldrich syndrome, a sex-linked immunodeficiency with only partial T-cell and B-cell–responsive functions. To prepare for a bone marrow transplant and avoid rejection of grafted cells, his immune system was stimulated and synchronized, and then its functions were ablated with a massive dose of cyclophosphamide. His histocompatible sister served as bone marrow cell donor. No graft-versus-host reaction ensued; 6 weeks later he was thriving and found to be chimeric.
1. Gatti R, Meuwissen HJ, Allen HD, Hong R, Good RA. Immunologic reconstitu-tion of sex-linked lymphopenic immunological immunodeficiency. Lancet 1968;292:1366-9.
2. Bach FH, Albertini RJ, Joo P, Anderson JL, Borton MM. Bone-marrow transplantation in a patient with the Wiskott-Aldrich syndrome. Lancet 1968;292:1364-6.
Images
Robert A. Good, MD (courtesy of the National Library of Medicine).
Fritz H. Bach, MD (courtesy of the University of Wisconsin-Madison Archives).
A major lead to elucidating the association of lymphoid tissue cells and the immune response was provided by poultry scientist Glick (1927-2009). In 1956, with associ-ates at Ohio State University, Glick1 demonstrated that surgical removal of the bursa of Fabricius, an avian lymphoid organ in the lower intestine, in 2-week old chicks led to their subsequent inability to produce specific antibodies to immunizing Salmonella typhimurium. Additionally discovered was that bursectomy in a later period of life after hatching, when the bursa began to atrophy, did not affect antibody production in the chicks. The finding suggested that, after differentiation and maturation in the bursa, antibody-producing lymphocytes relocate systemically. Glick’s seminal observation led to studies of thymus and bone marrow control of antibody-forming lymphocytes. Investigating outcomes of thymectomy in mice at the Chester Beatty Institute in London in 1961, Miller2 demonstrated a lateral functional role of thymus-derived lymphocytes in immune genesis and develop-ment. Neonatally thymectomized mice were totally immunoincompetent, and if reaching maturity, they exhibited serious immunologic defects. Adult thymecto-mized mice were unaffected.
1. Glick B, Chang TS, Japp RG. The bursa of Fabricius and antibody production. Poult Sci 1956;35:224-5.
2. Miller JFAP. Immunological function of the thymus. Lancet 1961;ii:748-49. Images
Bruce Glick (gift of Dr Glick).
Jacques F. A. P. Miller (gift of Dr Miller).
B LYMPHOCYTES, LYMPHOID ORGANS,
AND IMMUNE RESPONSES
In an attempt to demonstrate the existence of antibody-forming cells in the mouse thymus in 1966, Claman1 (1930- ) provided a landmark in lymphocyte immunobi-ology. With associates at the University of Colorado, he innovatively used a tissue culture system to assay the production of antibodies to sheep erythrocytes by spleen fragments from irradiated nonimmunized mice injected with thymus, bone marrow, or spleen cells from immunized donors. They found that a combination of thymus and bone marrow–derived immune cells produced an amount of specific hemolysin equal to that produced by immune spleen cells. When injected with immune marrow calls alone, no antibodies were produced by the recipients; injected thymus-derived cells alone generated only slight antibody activity.
A linear increase in activity was noted with a constant amount of thymus cells injected with increasing amounts of marrow cells. Combinations of thymus and marrow cells resulted in greater activity than could be accounted for by their summation. The interpretation was that a synergistic 2-cell “effector” and “axillary” system is required for optimal antibody production. Later studies confirmed that concept with designation of B (bursal equivalent or bone marrow) lymphocytes and T (thymus or thymic-dependent) lymphocytes as descriptors for effector and axillary cells, respectively.
1. Claman HN, Chaperon EA, Triplett RF. Thymus-marrow cell combinations: synergism in antibody production. Proc Soc Exp Biol Med 1966;122:1167-71. Image
Henry N. Claman, MD (gift of Dr Claman).
