Tolerance to noninherited maternal antigens, reproductive microchimerism and regulatory T cell memory: 60 years after 'Evidence for actively acquired tolerance to Rh antigens'.

Compulsory exposure to genetically foreign maternal tissue imprints in offspring sustained tolerance to noninherited maternal antigens (NIMA). Immunological tolerance to NIMA was first described by Dr. Ray D. Owen for women genetically negative for erythrocyte rhesus (Rh) antigen with reduced sensitization from developmental Rh exposure by their mothers. Extending this analysis to HLA haplotypes has uncovered the exciting potential for therapeutically exploiting NIMA-specific tolerance naturally engrained in mammalian reproduction for improved clinical outcomes after allogeneic transplantation. Herein, we summarize emerging scientific concepts stemming from tolerance to NIMA that includes postnatal maintenance of microchimeric maternal origin cells in offspring, expanded accumulation of immune suppressive regulatory T cells with NIMA-specificity, along with teleological benefits and immunological consequences of NIMA-specific tolerance conserved across mammalian species.

[The international network and Italian modernization. Ruggero Ceppellini, genetics, and HLA]. / NETWORK INTERNAZIONALI E MODERNIZZAZIONE ITALIANA. RUGGERO CEPPELLINI, LA GENETICA E L'HLA.

The paper reconstructs the scientific career of Ruggero Ceppellini, focusing especially on his role in the discovery of the genetic system underlying the Human Leucocyte Antigen. From his earliest investigations in blood group genetics, Ceppellini quickly became an internationally acknowledged authority in the field of immunogenetics--the study of genetics by means of immunological tools--and participated to the endeavor that ultimately yelded a new meaning for the word: thanks to the pioneering research in the HLA field, immunogenetics became the study of the genetic control of immune system. The paper will also place Ceppellini's scientific work against the backdrop of the modernization of Italian genetics after WWII, resulting from the efforts of a handful of scientists to connect to international networks and adopting new methodologies in life sciences.

A personal perspective: 100-year history of the humoral theory of transplantation.

The humoral theory states that antibodies cause the rejection of allografts. From 1917 to 1929, extensive efforts were made to produce antibodies against tumors. It was finally realized that the antibodies were produced against the transplant antigens present on transplantable tumors, not against the tumor-specific antigens. To get around this problem, inbred mouse strains were developed, leading to identification of the transplant antigens determined by the H-2 locus of mice. The antibodies were hemagglutinating and cytotoxic antibodies. The analogous human leukocyte antigen system was established by analysis of lymphocytotoxic alloantibodies that were made by pregnant women, directed against mismatched antigens of the fetus. The human leukocyte antigen antibodies were then found to cause hyperacute rejection, acute rejection, and chronic rejection of kidneys. Antibodies appeared in almost all patients after rejection of kidneys. With Luminex single antigen bead technology, donor-specific antibodies could be identified before rise in serum creatinine and graft failure. Antibodies were shown to be predictive of subsequent graft failure in kidney, heart, and lung transplants: patients without antibodies had superior 4-year graft survival compared with those who did have antibodies. New evidence that antibodies are also associated with chronic failure has appeared for liver and islet transplants. Four studies have now shown that removal or reduction of antibodies result in higher graft survival. If removal of antibodies prevents chronic graft failure, final validation of the humoral theory can be achieved.

Estudo de Associação entre o Sistema HLA e a Hanseníase / Study of association between alleles and haplotypes of the hla system and leprosy

A hanseníase é uma doença infecciosa crônica causada pelo Mycobacterium leprae, um parasita intracelular obrigatório com tropismo para Macrófagos na pele e células de Schwann nos nervos periféricos. As manifestações clínicas da hanseníase correspondem ao tipo de resposta imune do hospedeiro ao patógeno para conferir suscetibilidade. Muitas doenças têm sido relacionadas com o sistema HLA devido à sua importância na resposta imune adaptativa. Diversos estudos genéticos, em diferentes populações, têm sido realizados com o propósito de associar o HLA-DRB1 com a ocorrência da hanseníase per se e suas formas clínicas. Porém, os trabalhos realizados com HLA classe I são limitados. O presente estudo teve como objetivo analisar possíveis associações entre os alelos e haplótipos HLA classe I, além do polimorfismo TNF -308G>A e a hanseníase per se. Dessa forma, um estudo de caso-controle foi realizado em uma população de 778 pacientes não relacionados, portadores de hanseníase e 661 controles residentes na mesma área geográfica do Rio de Janeiro. Inicialmente, foram identificadas as frequências alélicas e haplotípicas de HLA-A, HLA-B e HLA-C, assim como o polimorfismo TNF -308G>A, que foram comparadas entre os casos e controles. Posteriormente, foram identificadas as frequências dos haplótipos estendidos (HLA-A-B-C-DRB1-TNF -308G>A) e comparadas entre as duas populações do estudo.

Os resultados demonstraram uma associação entre os alelos HLA-A* 11 e HLA-A* 30 com a susceptibilidade à hanseníase (p= 0,009 e p= 0,017, respectivamente), enquanto os alelos HLA-A* 01, HLA-B27, HLA-B*50 e HLA-C*05 sugeriram uma associação com a resistência à doença (p= 0,029, p= 0,005, p= 0,002 e p= 0,039, respectivamente). As análises dos haplótipos revelaram associação significativa de HLA-A*11-B*15 (OR=6,15) e HLA-A*30-B*42-C*17 (OR=4,16) com a susceptibilidade à hanseníase, assim como o HLA-A*11-B*35-C*04 (OR=2,37), mas com perda de significância do teste quando corrigido para as covariáveis sexo e etnia (p=0,117). Por outro lado, os haplótipos HLA-A*01-C*06 (OR=0,34), HLA-B*27-C*02 (OR=0,10) e HLA-B*50-C*06 (OR=0,18) demonstraram associações significativas com a resistência à doença. Os resultados também mostraram que o genótipo GA do TNF -308 esteve associado com a proteção à hanseníase (OR=0,74), porém com o nível de significância considerado borderline quando corigido (p=0.06). Em relação ao haplótipo estendido, o estudo indicou associação entre HLA-A*02-B*07- C*07-DRB1*15-TNF -308G (OR=4,66) e HLA-A*03-B*07-C*07-DRB1*15-TNF -308G (OR=4.72) e a suscetibilidade à hanseníase, porém com perda de nível de significância quando corrigido para as covariáveis sexo e etnia (p=0,077 e p=0,101, respectivamente). Muitas dessas associações já foram encontradas em outras populações, confirmando a importância desse sistema no desenvolvimento da doença.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae that is an obligateintracellular parasite with tropism for Macrophages in the skin and Schwann cells in the peripheralnervous system. Clinical manifestations of Leprosy correlate with the type of immune responsefrom the susceptible host to the pathogen. The HLA system has been related to several diseases,due to its important role in the adaptive immune response. Several genetic studies of differentpopulations have been conducted to correlate susceptibility or resistance of the HLA-DRB1toleprosy per se and its clinical forms, whereas HLA class I studies are limited. This present studyaimed to analyze the possible association between alleles and haplotypes HLA class I and the TNF-308G>A polymorphism and leprosy per se. Therefore, we used a population-based case controlstudy with 778 unrelated patients with leprosy and 661 controls from de same geographic area ofRio de Janeiro. First, HLA-A, HLA-B and HLA-C were evaluated, resulting in the allele andhaplotype frequencies that were compared between cases and controls, as well as the TNF -308G>A polymorphisms. Lastly, the extensive haplotype frequencies (HLA-A-B-C-DRB1-TNF -308G>A) were performed and compared between both populations. Our results suggestedassociation of the HLA-A*11 and A*30 alleles and leprosy susceptibility (p=0.009 and p=0.017,respectively), whereas HLA-A*01; HLA-B*27; HLA-B*50 and HLA-C*05 appeared associatedwith resistance to leprosy (p=0.029; p=0.005; p=0.002 and p=0.039, respectively).

Analyses of thehaplotypes demonstrated significant association of HLA-A*30-B*15 (OR=6.15) and A*30-B*42-C*17 (OR=4.15) with susceptibility of leprosy, as well as the HLA-A*11-B*35-C*04 (OR=2.37),but did not significant level when adjusted for the covariates gender and ethnicity (p=0.117). Inopposite, HLA-A*01-C*06 (OR=0.34), B*27-C*02 (OR=0.10) and B*50-C*06 (OR=0.17)haplotypes demonstrated significant association with resistance to leprosy. Results also showed thatthe GA genotype of TNF -308 was associated to protection to leprosy (OR=0.74), but with thesignificance level considered “borderline” when adjusted (p=0.06). For the extensive haplotype, thestudy indicated association between HLA-A*02-B*07-C*07-DRB1*15-TNF -308G (OR=4.66) andHLA-A*03-B*07-C*07-DRB1*15-TNF -308G (OR=4.72) and susceptibility to leprosy, but withlost significance level when adjusted for the covariates gender and ethnicity (p=0.077 and p=0.101,respectively). Many of these associations have already been found in other populations withleprosy, which confirmed the importance of this system in the disease development.

A short history of HLA.

In 1958, just a little more than 50 years ago, an alloantigen present on human leucocytes was detected, which was to become the 'first' human leucocyte antigen (HLA); HLA-A2. Since then, we have seen a tremendous development of the HLA field, which has moved from histocompatibility to become one of the most central fields in basic and clinical immunology. This development is briefly reviewed in this article, focusing on some highlights of the history of HLA class I and II molecules and their role in immune responses. It is emphasized that the quick and extensive development of the HLA field is the result not only of excellent individual contributions by outstanding pioneers in the field, but also of an extensive international collaboration, in particular through the many international histocompatibility workshops. Admitting that it is too late to change the name now, it is concluded that instead of calling the HLA complex and similar complexes in other species the major histocompatibility complex, these gene complexes should better have been named the major immune response complex, the MIRC.

Jon Van Rood: pioneer at the crossroad of human leukocyte antigens and transplantation.

Jon Van Rood (born in 1926) has made major contributions to the fields of transfusion medicine as well as organ and stem cell transplantation. His group was the first to start unraveling the complexity of the human leukocyte antigen (HLA) system through collaborative studies that used panels of sera and leukocyte samples. Furthermore, using HLA typing, he introduced the first HLA-matched platelet transfusions and developed routine leukocyte depletion as a means to prevent HLA alloimmunization. Van Rood has also been active in the fields of kidney transplantation (Eurotransplant) and stem cell transplantation (Europdonor). He combined scientific laboratory research with application to clinical medicine. He retired from his university position in 1991 but remains active in the field.

The tortuous journey of a biochemist to immunoland and what he found there.

After starting out to become a physician, by a series of accidents I found myself at NIH in 1951 during its most productive growth phase. At age 26, I had a fully funded, independent laboratory and did not know what to work on. With advice from colleagues, I initiated a study of how penicillin kills bacteria. Twenty years later, my lab had outlined the structure and biosynthesis of the peptidoglycan of bacterial cell walls and had discovered that penicillin inhibited the terminal step in its biosynthesis catalyzed by transpeptidases. I then switched fields, moving to Harvard in 1968 and beginning the study of human HLA proteins. Twenty-five years later, the last half of which was spent in a stimulating collaboration with the late Don Wiley, our labs had isolated, crystallized, and elucidated the three-dimensional structures of these molecules and shown that their principal function was to present peptides to the immune system in initiating an immune response. More recently, the laboratory has focused on natural killer cells and their roles in peripheral blood and in the pregnant uterine decidua. It has been a wonderful scientific journey.

Women, pregnancy and serendipity: a personal story about the discovery of HLA.

The discovery of HLA was an adventure in many ways very much like the discovery of a new continent with many people entering it from different angles. This has been a truly global effort with laboratories from all over the world voluntarily collaborating. The picture that finally emerged of a highly complex genetic system and its role in biology and medicine was and is fascinating. I have been involved from almost the beginning in the HLA story and have watched--often from nearby--the breakthroughs insights that opened new aspects of HLA. A discovery is not a gradual process, but one, which goes with jumps and laps. I will therefore not give a chronological summing up what happened, but limit myself to turning points, the sudden flashes of insight, which made working in HLA so exciting and rewarding.

Discovery: HLA and disease.

This article is a personal account of the author's involvement in the discovery of HLA associations with ankylosing spondylitis; Reiter disease; acute anterior uveitis; and the arthropathies associated with psoriasis, chronic inflammatory bowel disease, and sarcoidosis.

The short story of HLA and its methods.

BACKGROUND: During the past 40 years, typing for the human leukocyte antigens (HLA) was done using serological techniques. Several improvements were achieved as to the efficiency and reliability of these techniques. One of the major drawbacks of serology, however, is the need of viable cells. Especially blood cells drawn from deceased donors, as are the usual source for typing of corneal donors, may have a grossly impaired viability and a reduced expression of antigens on their cell surface. This makes serological typing difficult and liable to errors. In the mid-1980s, molecular typing was first introduced in many laboratories. This first period dealt with the so-called restriction fragment length polymorphism method, a tedious method not suited for prospective typing. Only with the introduction of the polymerase chain reaction was the suitability of molecular techniques with respect to perspective typing achieved. METHODS: International workshops and the effort of many laboratories led to a standardization of the methods. External proficiency testing exercises on transplantation relevant procedures in the laboratories affiliated to transplantation centers and the introduction of an accreditation system in the USA and in Europe increased significantly the reliability of all relevant immunogenetical testing. RESULTS: To date, patients and prospective organ and tissue donors are typed in addition to serology also with molecular methods. Using these techniques, the reliability and reproducibility of HLA typing have reached levels of more than 98%. Even 8-day-old peripheral blood samples can now be typed routinely with these methods, formerly impossible by serology. CONCLUSION: The laboratories affiliated to the transplantation centers are ready for high reliability testing of all HLA markers required by the clinic according to the results of controlled clinical long-term follow-up studies.