Clonal expansion of CD4ϩ T cells is a characteristic finding in patients with RA and is only infrequently found in patients with psoriatic arthritis and healthy controls. Expanded CD4ϩ clonotypes are present in the blood, infiltrate into the joint, and persist over years. We have now addressed the question of whether the expanded clonotypes have unique functional and phenotypic properties which may explain the preferential in vivo expansion in RA. In contrast to most CD4 ϩ T cells, expanded clonotypes lacked the expression of the CD28 and CD7 cell surface molecules. Accordingly, the subsets of CD4 ϩ CD28 Ϫ (9.7 vs. 1.7, P ϭ 0.00002) and CD4 ϩ CD7 Ϫ T cells (21.5 vs. 12.6, P ϭ 0.018) were increased in RA patients compared with age-matched normal individuals. Despite the lack of CD28 expression, clonally expanded CD4 ϩ T cells were not anergic but proliferated in response to immobilized anti-CD3 and could be maintained in tissue culture. In vivo expanded CD4 ϩ T cells were autoreactive to ubiquitously distributed autoantigens. They responded in an autologous mixed lymphocyte reaction, and T cell clones isolated from selected patients proliferated to autologous peripheral blood adherent cells. These data suggest that in RA patients selected CD4 ϩ T cells which share the CD7 Ϫ CD28 Ϫ phenotype escape from peripheral tolerance. ( J. Clin. Invest. 1996. 97

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Presented is a retrospective outcome study of a 15-year single institutional experience with a contemporary cohort of patients with hypoplastic left heart syndrome and complex that underwent a “Giessen Hybrid” stage I as initial palliation. Hybrid approach consisting of surgical bilateral pulmonary artery banding and percutaneous duct stenting with or without atrial septum manipulation was developed from a rescue approach to a first-line procedure. Comprehensive Aristotle score defined pre-operative condition. Fifteen-year follow-up mortality is reported as occurring within the staged univentricular palliation or before and after biventricular repair. Hybrid stage I was performed in 154 patients; 107 should be treated by single ventricle palliation, 33 by biventricular repair (BVR), 7 received heart transplantation, and 7 were treated by comfort care, respectively. Overall 34 children died. The Aristotle score (mean value 18.2 ± 3) classified for univentricular circulations in newborns did not have statistical impact on the outcome. Two patients died during stage I (1.2 %), and the interstage I mortality was 6.7 %, and stage II mortality 9 %, respectively. Stage III was up to now performed in 57 patients without mortality. At 1 year, the overall unadjusted survival of HLHS and variants was 84 % and following BVR 89 %, respectively. The Fifteen-year survival rate for HLHS and variants was 77 %, with no significant impact of birth weight of less than 2.5 kg. In conclusion, Hybrid stage I fulfilled the criteria of life-saving approach. In our institution, Hybrid procedure replaced Norwood-staged palliation with a considerable mid- and long-term survival rate. Considering interstage mortality close surveillance is mandatory.

RA is a heterogeneous disease with variations in phenotype. Sex-associated factors influence disease severity as well as disease pattern. Because sex-related effects influence treatment goals, treatment responses, and side effects, they should be considered in clinical study design and analysis as well as in the treatment decisions for individual patients with RA.

Oligoclonality is a characteristic feature of CD4+ CD28- T cells which are expanded in some healthy individuals and in the majority of RA patients. The lack of CD28 expression is a common denominator of CD4+, CD8+, and CD4- CD8- T cells prone to develop clonal dominance. The limited TCR diversity of clonal CD4+ CD28- populations in RA patients suggests that these T cells recognize a limited spectrum of antigens. The fact that the majority of individuals with marked expansions and oligoclonality of CD4+ CD28- T cells are RA patients suggests a role for these unusual lymphocytes in the pathogenetic events leading to RA.

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Co-stimulation mediated by the CD28 molecule is considered critical in the activation of CD4+ T cells. In patients with rheumatoid arthritis and infrequently in normal individuals, CD4+ T cells lacking CD28 expression are expanded and contain clonogenic populations. To analyze whether these cells are independent of co-stimulatory requirements or whether they use co-stimulatory signals distinct from the CD28 pathway, we have compared CD4+ CD28+ and CD4+ CD28- T cell clones isolated from rheumatoid arthritis patients. Accessory cells supported the induction of CD25 expression as well as of proliferative responses after anti-CD3 cross-linking and prevented the induction of anergy in CD4+ CD28- T cell clones. In contrast to CD4+CD28+ T cells, the presence of accessory cells did not enhance the secretion of interleukin (IL)-2, interferon-gamma, or IL-4. The co-stimulatory signals did not involve CD28/CTLA-4-CD80/CD86 receptor-ligand interactions. The proliferative response of CD4+CD28- T cells could not be blocked by anti-CD2, anti-CD18, and anti-CD58 antibodies, suggesting that these receptor-ligand interactions cannot provide CD28- independent co-stimulation. Our data suggest that CD4+CD28- T cells require co-stimulatory signals for optimal induction of cell growth and CD25 expression as well as for the prevention of anergy. The co-stimulatory receptor-ligand interaction is independent of the CD28 pathway and may be involved in the oligoclonal expansion of the CD4+ CD28- T cell subset in rheumatoid arthritis.

Although this study has important shortcomings due to its retrospective nature and because important variables potentially influencing outcome were not available for a substantial amount of patients, these data suggest that classical infantile Pompe disease still remains a life-threatening condition associated with high morbidity and often dismal prognosis. Currently, a relevant number of patients do not benefit definitely from ERT.