Pathogenesis and treatment of HIV infection: the cellular, the immune system and the neuroendocrine systems perspective.

Infections with HIV represent a great challenge for the development of strategies for an effective cure. The spectrum of diseases associated with HIV ranges from opportunistic infections and cancers to systemic physiological disorders like encephalopathy and neurocognitive impairment. A major progress in controlling HIV infection has been achieved by highly active antiretroviral therapy (HAART). However, HAART does neither eliminate the virus reservoirs in form of latently infected cells nor does it completely reconstitute immune reactivity and physiological status. Furthermore, the failure of the STEP vaccine trial and the only marginal efficacies of the RV144 trial together suggest that the causal relationships between the complex sets of viral and immunological processes that contribute to protection or disease pathogenesis are still poorly understood. Here, we provide an up-to-date overview of HIV-host interactions at the cellular, the immune system and the neuroendocrine systems level. Only by integrating this multi-level knowledge one will be able to handle the systems complexity and develop new methodologies of analysis and prediction for a functional restoration of the immune system and the health of the infected host.

[Conception and course of eight pregnancies in five women on TNF blocker etanercept treatment]. / Konzeption und Verlauf von acht Schwangerschaften bei fünf Patientinnen unter TNF-α-Blockade mit Etanercept.

The introduction of tumor necrosis factor (TNF)-α inhibitors s in the late 1990s considerably broadened the treatment options for, and essentially contributed to the successful management of, rheumatoid arthritis (RA) and other immune-mediated inflammatory diseases. Nevertheless, their use during pregnancy is still controversially discussed since it remains unclear whether the benefits of treatment might be outweighed by potential teratogenicity or adverse effects on the course of pregnancy. In this case series report we describe the course and outcome of eight pregnancies in five women (four with RA and one with ankylosing spondylitis) at our private clinical practice treated with the TNF-α inhibitor etanercept at the time of conception and during pregnancy. The course was inconspicuous in six of the eight pregnancies; in one case a megacolon congenitum was diagnosed 2 weeks after birth, while one spontaneous abortion occurred in the 10th week of pregnancy after a disease flare following treatment discontinuation with etanercept in the 5th week of pregnancy. Based on our experience to date and the currently available literature data, we believe that continuation of treatment with TNF-α blockers is justified in pregnant patients with otherwise high disease activity and disease progression.

[Indications for eye examination of HIV patients--screening parameters for cytomegalovirus retinitis]. / Indikation zur Augenuntersuchung von HIV-Patienten--Screening-Parameter für CMV-Retinitis.

BACKGROUND: To reduce the burden of frequent visits at the physician we have checked (I) for which ocular manifestations in HIV-infection screening of asymptomatic patients is worthwhile and (II) which parameters may indicate patients at risk for CMV-retinitis. PATIENTS AND METHODS: The clinical data of 215 HIV-infected patients were analyzed retrospectively. Only those ocular manifestations were considered suitable for screening that (a) endanger vision, (b) are treatable, (c) can be diagnosed sufficiently early and (d) are common. Furthermore (1) CDC-stage, (2) CD4+ count, (3) HIV-retinopathy, (4) CMV-uria and (5) CMV-antibodies were checked for their usefulness in indicating patients at risk for CMV-retinitis. RESULTS: Ophthalmological screening of asymptomatic HIV-patients should focus on cytomegalovirus (CMV)-retinitis because early diagnosis of this common blinding disease improves the visual outcome. 85 of 215 HIV-infected patients had a CD4+ count less than 50 cells/microliters 25% of these patients developed CMV-retinitis (21/85). The risk for CMV-retinitis rose to 38% (13/34) when the low CD4+ count was accompanied by CMV-uria. The proportion of patients with CMV-retinitis did not increase when HIV-retinopathy had been diagnosed earlier (12/48 = 25%). CMV-serology and CDC-classification were not helpful in screening for CMV-retinitis. CONCLUSIONS: We recommend the following ophthalmological screening scheme for HIV-patients without ocular symptoms: (1) patients with a CD4+ count < 100 cells/microliters should be checked every third month and (2) those with a CD4+ count < 50 cells/microliters and CMV-uria every sixth week.

Common variable immunodeficiency (CVID) and MxA-protein expression in blood leucocytes.

The underlying immunopathogenic mechanism of CVID has been suspected to involve a chronic viral infection or an autoimmune condition. However, formal proof of viral infection is lacking. Measurement of MxA-protein in leucocyte lysates is a sensitive test for evaluating the activation of the host's interferon system. Both viral infections and autoimmune diseases such as systemic lupus erythematosus (SLE) strongly induce MxA-protein in peripheral leucocytes. We therefore examined 15 patients with longlasting hypogammaglobulinaemia for MxA-protein induction in vivo: 13 patients suffered from CVID, one from hyper-IgM syndrome, and one patient had chronic B lymphocytic leukaemia associated with immunoglobulin deficiency and chronic papilloma virus infection (condylomata accuminata). Only the latter patient exhibited a strong MxA-protein expression; two CVID patients were borderline positive, and the remaining 12 patients including the hyper-IgM syndrome were MxA-protein-negative. There was no relationship between MxA expression and low CD4/CD8 ratios or increased CD8/CD57+ T cell counts, although both conditions are often observed in CVID as well as in chronic viral infections. When exposed in vitro to interferon-alpha (IFN-alpha), peripheral blood leucocytes of four MxA-negative patients were capable of producing normal amounts of MxA-protein. Taken together, these results argue against a viral or autoimmune pathogenesis of CVID.

[Defects in the immunoglobulin producing cells in bone marrow of patients with variable immunodeficiency syndrome]. / Defekte der immunglobulinbildenden Zellen im Knochenmark von Patienten mit variablem Immundefektsyndrom.

The number of plasma cells, IgG+, IgA1+, IgA2+ and IgM+ cells were determined in bone marrow (BM) biopsies of 12 patients with common variable immunodeficiency syndrome (CVID) and 12 controls without signs of immunodeficiency. Controls had a median of 11 plasma cells/mm2, 76 IgG+, 76 IgA+ and 18 IgM+ cells/mm2 BM, respectively. Compared with the control group, the CVD patients showed a significant reduction of each cell type (p < 0.001). They also demonstrated a close correlation between low numbers of IgG+ and IgA+ cells in the BM and low IgG and IgA serum levels. In general, there was also a good correlation of the IgM+ cells and the respective IgM levels in the serum, except 2 CVID patients with normal IgM serum levels and subnormal numbers of IgM+ cells in the BM. Our results showed that there was an almost complete coincidence between the reduced numbers of Ig-producing cells in the BM and low serum levels of the respective Ig isotype. Thus, immunohistological analysis may be of additional help for the diagnosis of immunodeficiency.

Leukocytoclastic vasculitis and long-term remission in a patient with secondary AML and post-remission treatment with low-dose interleukin-2.

Interleukin-2 (IL-2) has been licensed for the treatment of renal cell carcinoma and is currently being evaluated as a therapeutic agent in hematological malignancies. It is associated with a variety of side effects due to induction of a nonspecific inflammatory response. However, phenomena of autoimmunity have also been reported. Here we describe a patient with secondary acute myeloid leukemia who developed a leukocytoclastic vasculitis during long-term post-remission treatment with very low doses of IL-2.

[Differential diagnostic aspects of lethal midline granulomas (granuloma gangraenescens]. / Differentialdiagnostische Aspekte des letalen Midline-Granuloms (Granuloma gangraenescens).

The lethal midline granuloma and limited Wegener's granulomatosis show clinical similarity, although they are of different etiology. The following case of a 53-year-old woman shows how difficult it is to establish the precise diagnosis of lethal midline granuloma. The diagnosis depends on the pathological finding of a lymphoma. The lymphoma can be differentiated in a T- or a B-cell lymphoma by immunostaining. However, the diagnostic yield of biopsies from the nose is not perfect. It would be, therefore, important to find other diagnostic criteria. The presence of the c-ANCA is a helpful tool, but in the case of limited Wegener's granulomatosis, it has a sensitivity of 50%. The prognosis of the lethal midline granuloma is poor even if an adequate radiation therapy is instituted.

p-ANCA of undefined specificity in ulcerative colitis: correlation to disease activity and therapy.

Sera of 108 patients with chronic inflammatory bowel disease (IBD) and 13 sera from patients with other gastrointestinal diseases were screened for antibodies against neutrophil cytoplasmic antigens (ANCA) by an indirect immunofluorescence test. 37 out of 64 sera (58%) from patients with ulcerative colitis (UC) produced a fine granular and perinuclear ANCA staining pattern ("snowdrift-like" p-ANCA) clearly different from the cytoplasmic ANCA fluorescence (c-ANCA) seen in active Wegener's granulomatosis (WG) and the typical p-ANCA pattern produced by anti-myeloperoxidase (MPO) autoantibodies. Only 1 of 44 sera from patients with Crohn's disease (CD) and none of the control sera showed positive "snowdrift-like" p- ANCA reactions. 31 out of the 37 p-ANCA positive sera (84%) were obtained from patients with high disease activity with and without longterm high dose steroids. p-ANCA titers became negative after longterm steroid therapy and following complete colectomy.

[A new type of ANCA in sera of patients with ulcerative colitis: effects of therapy and disease severity on serum titer]. / Ein neues ANCA-Muster in Seren von Patienten mit Colitis ulcerosa: Einfluss von Therapie und Krankheitsaktivität auf die Höhe der Serumtiter.

Sera of 108 patients with chronic inflammatory bowel disease (IBD) and 13 control sera were screened for antibodies against neutrophil cytoplasmic antigens (ANCA) by an indirect immunofluorescence test. 37 out of 64 sera (58%) from patients with ulcerative colitis (UC) produced a fine granular and perinuclear ANCA staining pattern (p-ANCA) clearly different from the typically diffuse and granular cytoplasmic ANCA fluorescence (c-ANCA) seen in active Wegener's granulomatosis (WG). Only 1 of the 44 sera from patients with Crohn's disease and none of the control sera showed positive p-ANCA reactions. Only 1 of the 64 CU sera was positive for antinuclear antibodies, and another one showed a positive reaction in the anti-proteinase-3 ELISA which is specific for WG. Antibodies against myeloperoxidase were negative in the CU sera. 31 out of the 37 p-ANCA-positive sera (84%) were obtained from patients with high disease activity. p-ANCA titers became negative after long-term steroid therapy and after complete colectomy. These preliminary data suggest that ANCA screening may be of value in differentiating IBD and in monitoring disease activity and drug effects in UC patients.

[Immunologic defects in the lymphatic system of the intestinal mucosa in common variable immunodeficiency (CVID) syndrome]. / Immundefekte des lymphatischen Systems der Darmschleimhaut bei variablem Immundefektsyndrom (common variable immuno deficiency (CVID)-Syndrom).

The humoral immune system of the intestinal mucosa of patients with common variable immuno deficiency (CVID) syndrome was studied immunohistologically using antibodies against immunoglobulin (Ig) A1-2, M and G1-4, against the J chain and the secretory component. In 9/13 CVID-patients IgA-positive cells were totally absent whereas a total IgM-defect was found only in 3/14 patients. Considerable numbers of J chain-positive cells were present in all CVID-patients irrespective of the extent of the Ig-defect indicating the presence of early B-cells unable to differentiate and to produce Ig. There was a strong expression of the secretory component in the cytoplasm and at the surface of enterocytes even in those CVID-patients who were totally defective in IgA- and IgM-positive cells.

A new type of perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) in active ulcerative colitis but not in Crohn's disease.

Sera of 64 patients with chronic inflammatory bowel disease (IBD) were screened for antibodies against neutrophil cytoplasmic antigens (ANCA) using an indirect immunofluorescence technique on ethanol-fixed human neutrophil granulocytes. 20 of 34 sera (59%) from patients with ulcerative colitis (UC) produced a fine-granular and perinuclear ANCA staining pattern (p-ANCA) clearly different from the typical diffuse and granular cytoplasmic ANCA fluorescence (c-ANCA, synonym ACPA) seen in active Wegener's granulomatosis (WG). The majority of the 20 p-ANCA positive UC patients had a high inflammatory disease activity. Among the 14 p-ANCA negative UC patients nine were without steroids; five of them had active disease, two were inactive and two had previously undergone colectomy. The remaining five patients still had active disease but received steroids for more than 4 weeks. Only 3 of the 30 sera from patients with Crohn's disease (CD) showed positive p-ANCA reactions. To narrow the specificity of the p-ANCA reaction all 64 sera were tested by ELISA for antibodies against anti-proteinase-3 (WG specific) and on HEp-2 cells for antinuclear (ANA) and anticytoplasmic antibodies. Ten p-ANCA positive UC sera were also tested in a myeloperoxidase ELISA. Only one UC serum reacted positively in the proteinase-3-ELISA and another one produced a weakly positive anti-nucleolar ANA fluorescence on HEp-2 cells. None of the tested sera reacted with myeloperoxidase suggesting that the p-ANCA staining pattern of granulocytes is not restricted to anti-myeloperoxidase antibodies as reported in the literature.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effects of IL-2 and IL-6 on the immunoglobulin synthesis of lymphocytes from CVID patients]. / Effekte von IL-2 und IL-6 auf die Immunglobulin-synthese von Lymphozyten von CVID-Patienten.

Peripheral blood lymphocytes from five hypogammaglobulinemic patients suffering from common variable immunodeficiency (CVID) were stimulated with Staphylococcus aureus Cowan I (SAC) and pokeweed mitogen (PWM). The assays were substituted with interleukin-2 (IL-2) and interleukin-6 (IL-6) in different combinations. In three patients who were deficient for IgM in vivo a combination of SAC and IL-2 induced a normal IgM synthesis in vitro. In these patients a deficient IL-2 synthesis is probably the cause of CVID. In only one patient a "class switch" from IgM to IgG was detectable. Stimulation with PWM which is T-cell-dependent induced in one out of the five patients a normal IgM synthesis. Another CVID patient showed no defect in IgM or IgG synthesis in vitro. With these in vitro assays it seems possible to identify CVID patients who might profit from a therapy with human IL-2 in vivo.

[ACPA reaction in atypical Wegener's disease. Diagnostic test]. / ACPA-Reaktion bei atypischem Morbus Wegener. Diagnoseweisender Test.

Clinical and biopsy findings in six patients (aged 29-64 years), suspected of having Wegener's granulomatosis, were not diagnostic. Cardinal signs were skin necroses, isolated deficits of cranial nerves, sudden amaurosis, renal failure with shunt sepsis and lung opacities suspicious of tumour. Only positive tests for anti-cytoplasmatic antibodies (ACPA) in serum made the diagnosis and led to appropriate treatment. This simple yet highly specific immunofluorescence test should be performed in every case of vasculitis of uncertain cause, even if typical clinical signs of Wegener's granulomatosis are at first absent.