[Uterine anomalies in women with recurrent pregnancy loss]. / A méhüreg anatómiai rendellenességei habituális vetélokben.

INTRODUCTION: One percent of couples trying to have children are affected by recurrent miscarriage. These pregnancy losses have different pathogenetic (genetic, endocrine, anatomic, immunologic, microbiologic, haematologic and andrologic) backgrounds, but recurrent miscarriage remains unexplained in more than half of the affected couples. AIM: To explore risk factors for recurrent pregnancy loss the authors studied the incidence of anatomic disorders of the uterine cavity occur in Hungarian women with recurrent miscarriage. METHOD: Medical records of 152 patients with recurrent miscarriage were analyzed retrospectively. In order to explore disorders of the uterine cavity hysteroscopy or 3-dimensional sonography in 132 women, hysterosalpingography in 16 and hysterosalpingo-sonography in 4 patients were used. RESULTS: Incidence of anomalies in the uterine cavity was found in women with recurrent miscarriage to be 15.8%. A variety of the uterine anomalies was found including uterine septum in 6.5%, endometrial polyp in 2.6%, arcuate and bicornuate uteri both in 2% and 2%, submucosal myoma in 1.3 %, and intrauterine synechiae in 1.3%. CONCLUSIONS: These findings suggest that morphologic disorder of the uterine cavity is frequent in Hungarian women with recurrent miscarriage. Therefore, assessment of the uterine anatomy is recommended in such patients.

Autoimmune-associated HLA-B8-DR3 haplotypes in Asian Indians are unique in C4 complement gene copy numbers and HSP-2 1267A/G.

The classical AH8.1 (HLA-A1-B8-DR3-DQ2) is the most common Caucasian haplotype, associated with several autoimmune diseases, immunologic hyperreactivity and rapid progression to the acquired immunodeficiency syndrome. However, in Asian Indians, there are multiple unique B8-DR3 haplotypes that are associated with autoimmunity and differ significantly from the common Caucasian AH8.1. The Indian HLA-A1-B8-DR3 is therefore referred to as an AH8.1 variant. The aims of this study were to compare C4A and C4B copy numbers and to identify alleles in HSP70-2 and LTA in these haplotypes. The Indian B8-DR3 haplotypes differ from the Caucasian AH8.1 at C4A and HSP70-2 loci. The Indian B8-DR3 haplotypes have 1 copy each at C4A and C4B, while the Caucasian AH8.1 has 1 copy at C4B but no C4A gene. Moreover, the Indian and Caucasian B8-DR3 haplotypes had HSP70-2 1267 *A, and *G alleles, respectively. By contrast, the LTA 252 *G allele occurred both in the Indian and Caucasian haplotypes. The Indian haplotypes also contained Bf*F and TNF-308*G that were different from the Caucasian equivalents Bf*S and TNF-308*A. These differences and previous studies support the hypothesis that B8-DR3-DQ2 haplotypes in Asian Indian population might have originated independently of Caucasian AH8.1 selectively through recombination and mutations. Because autoimmune disease associations are shared among these otherwise diverse haplotypes, these data strongly suggest that some shared component(s) of all these associated haplotypes may be playing a key role in such associations.

[Intravenous immunoglobulin treatment of recurrent spontaneous abortion with immunopathological background]. / Az immunpatológiai hátteru habituális vetélés kezelése terhesség alatti intravénás immunglobulinnal.

INTRODUCTION: Recurrent spontaneous abortion (RSA) is diagnosed if three or more spontaneous abortions follow each other typically in the first trimester. The root cause of miscarriages often can not be found. A significant proportion of this unexplained RSA cases may be caused by immunopathological failure. AIM: A multicentric clinical study started in 2000 to introduce an immunological screening protocol for patients suffering in idiopathic habitual abortion, and to use immunotherapy for their treatment if immunological background was defined. METHOD: The general checkup of the patients was managed based upon a detailed protocol, with which non-immunopathological reasons for RSA were excluded. The unexplained RSA cases underwent an immunological checkup including cellular and humoral immunological, immunogenetic and autoimmune examinations. Based upon these parameters, the immunopathological background of RSA was certified or excluded. In the confirmed immunopathological cases intravenous immunoglobulin (IVIG) therapy was applied during their next pregnancy, with continuous monitoring of the immunological parameters. RESULTS: 120 patients with RSA were examined, and 32 of them got IVIG therapy during their next pregnancy. In 72% of cases (23/32) IVIG treatment for RSA with immunopathological alloimmune background was successful, with the outcome of healthy newborn. Of the 9 unsuccessful cases, in 6 patients subsequently additional non-immunopathological reasons were diagnosed for their RSA. IVIG treatment of patients with clear alloimmune background was successful in 88.5% (23/26). CONCLUSION: Results show that immunopathological checkup and immunotherapy is a useful treatment in the modern medicine for the patients with unexplained RSA. However the success of this method depends on the adherence of the checkup protocol, because unsuccessful therapy of non-clear cases can reduce the efficiency.

The complexity of immune and alloimmune response.

Alloimmune response induced by foreign histoincompatible alloantigens is a complex phenomenon possessing mechanisms, characteristics to innate and adoptive immune response. It is also modified by various immunregulating exocrine and autocrine factors. Starting the new time period of functional genomics the knowledge of human genes' structure needs a more clear insight not only about the function and contribution of genes but their historical background, origin and importance in the phylogenesis. Comparative immunology comes into focus of interest helping to understand the complexity of immune and alloimmune response. It is almost unbelievable that immune functions as phagocytosis and cytokine production like IL-1 and TNF have already emerged 700 million years ago in starfishes and sponges. Functions--including recruitment of coelomocytes, killing of micro-organisms by lysosome-like enzyme activity, opsonization by complement analogous proteins and oxidative burst function--remained unchanged during phylogenesis and could be found not only in insects but in mammals as well as representatives of innate immunity. The importance of these molecules is reflected in homology of conservative regions. One of the biggest evolutionary steps happened 500 million years ago when fish developed a jaw in the Placoderms species. This fact led to the development of gut associated immune system. The system was the basis to create the genetic material for recombination and mutation to establish variability and diversity of proteins, as immunoglobulins. It is interesting to lean how diversity of immunglobulins in sharks is insured by joining of blocks of V, D, J and C genes, in contrast to humans, where those genes are located on different chromosome regions. These differences are associated with an immediate production of specific immunglobulin or a slower one combined with immunologic memory. Similar development could be found in T cell antigen specific receptors, too. Concerning the establishment of adoptive immunity by emergence of genetic recombination, which allowed the production of a huge diversity of specific antigen binding proteins, another structure developed parallel from the histoglobin molecule. This protein was created to catch peptide particles which split from the proteins originating from microorganisms, viruses or foreign cell compartments. The cave-like groove capturing the different peptides represented a huge variability. These histocompatibility molecules emerged from this ancient structure for more than 300 million years ago. The genetic family responsible for their synthesis became the most complex gene family including many other genes involved in the immune response. The polymorphic character of the histocompatibility protein is responsible for the capture of the relevant peptides fitting best to the allotype-determined groove. In certain species the same function could be filled by different ancient molecules with the same success. Dendritic cells and their importance in differentiation and antigen presentation became in the focus of interest in the last decade. They have lymphoid and myeloid origin, mature and less differentiated subtypes with characteristic CD markers and cytokine profile. Their function and origin from the stem cell subpopulation is an important example how nature influences the development of immunity to the accommodation and survival to the always changing environment. The new molecular techniques will help to get closer to understand the function of genes regulating immune response and modify them.

The pattern of cytokine gene expression in human colorectal carcinoma.

Systemic and local cytokine environment may modulate the immunogenicity of colorectal cancer cells, and affect anti-tumor immune functions of tumor-infiltrating lymphocytes. We therefore investigated cytokine mRNA expression patterns in tumors and peripheral blood mononuclear cells (PBMC) from patients with colorectal adenocarcinoma. IL-2, IFN-gamma, tumor necrosis factor-alpha (TNF-alpha), IL-4, IL-6, IL-8, IL-10 and IL-1 beta mRNAs in single cell suspension of freshly isolated colorectal cancer tissue were studied by RT-PCR. Frequencies of cytokine gene expression were compared to those in normal colonic mucosa from tumor patients. The frequencies of IL-2, IFN-gamma, IL-4 and IL-10 gene expression were also determined in peripheral blood mononuclear cells from patients with colorectal adenocarcinoma and compared to those of healthy individuals. Tumor samples were more frequently positive for IFN-gamma, IL-2, TNF-alpha and IL-10 gene expression than normal mucosa (p=0.0001, p=0.0118, p=0.001 and p<0.0001, respectively). Frequencies of IL-2 and TNF-alpha gene expressions were significantly higher in tumors with a diameter <5 cm, than in those with a diameter >5 cm. The genes for IL-6, IL-1 beta and IL-8 were commonly expressed in both tumor tissue and normal colonic mucosa. IFN-gamma transcripts were detected in more PBMC samples from patients with colorectal cancer than those from normal controls (p=0.0449). Thus, colorectal cancer tissue is characterized by a specific pattern of cytokine gene expression. It is likely that multiple interactions between pro- and anti-inflammatory cytokines regulate tumor growth and the functional activity of tumor-infiltrating lymphocytes.

The induction of active or peripheral tolerance in organ transplantation: dream or reality.

Immunological tolerance induction is one of the most exciting research fields in experimental and clinical transplantation. From the first discovery of Nobel Prize awarded to L. Brent and P. Medawar, beside the classical induction of central tolerance in newborn mice, several methods, interventions and compounds have been introduced with a view to establishing tolerance. It was clarified that the mechanisms have different characteristics for central and peripheral or active/operative transplantation tolerance. In the case of the latter, tolerance was accompanied with mixed chimeric state. In the last decade, new compounds, such as monoclonal antibodies specific for membrane receptors on T- and APC cells responsible for signal 1 and signal 2 functions have been employed to induce operative tolerance. Among various methods and immunosuppressive interventions, non-myeloablative treatments combined with hematopoietic stem cell infusion showed the most effective results. This form of induction is associated with the well known "beneficial transfusion effect" in kidney transplantation. Based on the experimental achievements of clinical organ transplantation, various protocols have been introduced to induce peripheral tolerance. In spite of the short observation time of this progress the results seem to be promising, first of all, in the prolonged rejection-free survival time of the graft and the possibility to withdraw the immunosuppressive treatment altogether.

[Advantages of living donor kidney transplantation; possibilities in the national transplantation program]. / Az élo donoros vesetranszplantáció elonyei. Lehetoségeink a hazai transzplantációs programban.

The review paper summarizes the advantages of the living donor kidney transplantation aiming that this kind of activity should get more support in Hungary. It is a general phenomenon overall the world, that there is no more possibility to increase the number of cadaver transplantations, and the outcome of them is also worsening because of the accumulation of aged patients with long time period of dialysis treatment. The paper points out the better results of living donor kidney transplantation underlining that the kidney long term survival, in general, is 10% over the cadaver kidney survival with significant less complication. The indication of living related and unrelated donor kidney transplantation is reported and the harmless of donor kidney removal demonstrated. An important part of the review contains the ethical, legal and social issue of the living donation, moreover, its economical benefit. It shows that in certain countries the living donation becomes in the forefront of the transplantation activity, which demonstrates from statistical point of view the overall benefit in comparison to cadaver transplantation. Based on the experience of those countries, which are performing this type of transplantation for a long time ago recommendation is given what should be the methodology to increase the activity in this field of transplantation.

[Methods of screening for adult celiac disease in patients attending ambulatory care service in immunology]. / A felnóttkori coeliakia felismerésének lehetósége szúróvizsgálatok alkalmazásával immunológiai szakambulancián jelentkezó betegekben.

INTRODUCTION: Coeliac disease (gluten sensitive enteropathy) is a very frequent disease appearing in variegated clinical form. In the last decade--concerning the immunogenetic and immunopathological aspects of the disease many of new recognition came to alight. AIM: As the disease can lay hidden in its non classical manifesting form for a very long time, authors wished to study the efficacy of screening, which may be introduced for patients attending immunological outpatient care service. PATIENTS, METHODS AND RESULTS: In the frame of nation-wide patient care, out of the 200 potential patients sent for immunological check up, various form of coeliac disease was diagnosed in 20 cases. Among these cases there are two--presented for the first time--which are connected to bone marrow transplantation. Based on the immunogenetics and autoantibody serology as well as on small intestine biopsies the following conclusions were made. CONCLUSION: 1. Coeliac disease in Hungary is very frequent. Hidden disease should be considered first of all in cases of malabsorption symptoms. 2. Demonstration of autoantibodies on wide-scale palette helps to state the diagnosis based on the systematic auto-immune disease connection. 3. Study of Human Leukocyte Antigen allotype (HLA-DQA1*0501/DQBI*02) applied as marker can considerably support the suspicion of disease. 4. Histology test of the small intestine cannot be omitted.

Alloimmune and autoimmune background in recurrent pregnancy loss - successful immunotherapy by intravenous immunoglobulin.

PROBLEM: Immunotherapies [leukocyte immunization, intravenous immunoglobulin (IVIG)] introduced to treat women with recurrent spontaneous abortions (RSA) have still controversial results in most clinical trials. A selection of these patients would be advantageous for higher efficacy. METHOD OF STUDY: A complex immunological panel assay was offered to patients with reproductive failure without any other known cause. We focused here on the cellular immunological parameters. RESULTS: High cytotoxic T lymphocyte precursor frequency and cell-mediated cytotoxic activity and a rather high natural killer cell activity were found in alloimmune RSA patients. Thirty-two patients were investigated by immunological assays and in 78% of the women an alloimmune background could be defined. The efficacy of IVIG treatment was 96% in this group. CONCLUSIONS: The novel cellular immunological assays proved to be favourable for the indication of RSA patients and showed the usefulness of this selection process for effective immunotherapy.