The discovery of agammaglobulinaemia in 1952.

UNLABELLED: Fifty years ago a new disease, agammaglobulinaemia, was described. This was made possible by a great number of preceding technical innovations and theories on different fields of research, in particular haematology, microbiology/immunology and basic sciences. The widely used name "Bruton disease" credits one single man with a new observation which, however, was simultaneously made by several physicians. Agammaglobulinaemia was the first example of an immunodeficiency syndrome (IDS). Based on new facts, new ideas emerged which in turn gave rise to innovative research, concerning both clinical observations and basic problems. Many similar diseases, usually resulting from a genetic defect, were described. Since 1970, an International Committee appointed by the WHO, has, with periodic reassessments, been working on the classification of the syndromes. All participants of an efficient immune reaction can be deficient in individual patients, that is: antibodies, lymphocytes, phagocytes and complement. Basic scientists presented striking results concerning the structure and action of all elements mentioned above. CONCLUSION: mutual stimuli coming from observations in families and from gene technology have resulted in the elucidation of the genetic defects of most IDS. Recent results of genetic engineering seem to justify some hope for success in therapy.

Cellular immunology in a historical perspective.

Bruton's XLA and DiGeorge syndrome patients show that two basic immune systems are distinct from each other in humans - thymus-dependent cell-mediated immunodeficiencies vs. antibody-based immunodeficiencies. The appendix-sacculus lymphoid organ of rabbits, like the bursa of Fabricius, represents a central lymphoid organ. Chronic granulomatous disease of childhood (CGD) revealed that phagocytosis killing of catalase-positive microorganisms employ oxidative burst. Bone marrow transplantation (BMT) proved life saving in severe combined immunodeficiency (SCID). The first BMT cured XSCID and the second BMT cured a complicating aplastic anemia launching BMT as a treatment of many diseases. Now 75 fatal diseases have been cured by myeloablative BMT. BMT also cured experimental autoimmune diseases. BMT alone did not cure lupus with polyarthritis in MRL/lpr mice or polyarthritis in NZB/KN mice, but BMT plus bone (stromal cell) transplants cured these diseases. Autoimmune diseases and lethal glomerulonephritis were prevented or cured in BXSB mice by mixed allogeneic plus syngeneic BMT. X-linked Hyper IgM syndrome (XHIM) was also cured by BMT from a 2-year-old MHC-matched sibling donor. Nonmyeloablative BMT plus mesenchymal stem cells (stromal cells) was effective treatment for a form of collagen-vascular disease and also a lethal form of hypophosphatasia. Mannan-binding lectin, an opsonin that activates the complement system when mutated and at low levels in blood, opens a door to frequent infections throughout childhood and adult life. This new immunodeficiency is based on genetic mutations that involve a native defense system.

The lesson of agammaglobulinemia 40 years after Bruton's discovery.

Forty years after Bruton's discovery, the spectrum of primary defects of immunoglobulins has been largely extended and characterized. An increasingly more accurate recognition of the basic pathogenetic mechanisms of disease has helped to design more effective drugs and therapeutic strategies for patients with both primary and secondary immune deficiencies. In recent years, major advances in molecular biology have allowed characterization of the genetic basis of many primary immunodeficiencies, resulting in more accurate genetic counseling and leading to the first successful application of genetic therapy to the treatment of a human disease.

[History of immunologic deficiency]. / Storia dei deficit immunitari.

The description of agammaglobulinemia by O. Bruton in 1952 and later clinical studies by R. Good preceeded by sporadic clinical observations on deficits in the immune function associated with hyponutrition, nephrosis and tumors or with inborn errors of metabolism have all made their contribution to the emerging of the concept of immunological deficiency diseases. The clinical-pathogenetic description of immunological deficiency diseases has played a fundamental role in the understanding of the anatomo-functional bases of the immune system and research work on the phylogenetic and ontogenetic evolution of the immune response. Various methodologies, from the idea of experimentum naturae to molecular pathology, combine to define and direct this research, the result of an ongoing interaction between the hospital and the laboratory. This leads to a necessary theoretical-practical synthesis and contributes to the consolidation of an immunologically-directed medicine.