A single autoimmune T cell receptor recognizes more than a million different peptides.

The T cell receptor (TCR) orchestrates immune responses by binding to foreign peptides presented at the cell surface in the context of major histocompatibility complex (MHC) molecules. Effective immunity requires that all possible foreign peptide-MHC molecules are recognized or risks leaving holes in immune coverage that pathogens could quickly evolve to exploit. It is unclear how a limited pool of <10(8) human TCRs can successfully provide immunity to the vast array of possible different peptides that could be produced from 20 proteogenic amino acids and presented by self-MHC molecules (>10(15) distinct peptide-MHCs). One possibility is that T cell immunity incorporates an extremely high level of receptor degeneracy, enabling each TCR to recognize multiple peptides. However, the extent of such TCR degeneracy has never been fully quantified. Here, we perform a comprehensive experimental and mathematical analysis to reveal that a single patient-derived autoimmune CD8(+) T cell clone of pathogenic relevance in human type I diabetes recognizes >one million distinct decamer peptides in the context of a single MHC class I molecule. A large number of peptides that acted as substantially better agonists than the wild-type "index" preproinsulin-derived peptide (ALWGPDPAAA) were identified. The RQFGPDFPTI peptide (sampled from >10(8) peptides) was >100-fold more potent than the index peptide despite differing from this sequence at 7 of 10 positions. Quantification of this previously unappreciated high level of CD8(+) T cell cross-reactivity represents an important step toward understanding the system requirements for adaptive immunity and highlights the enormous potential of TCR degeneracy to be the causative factor in autoimmune disease.

Chronic fatigue syndrome: an update focusing on phenomenology and pathophysiology.

PURPOSE OF REVIEW: Chronic fatigue syndrome is a controversial condition especially concerning its clinical definition and aetiopathogenesis. Most recent research progress has been made in phenomenology and pathophysiology and we focused our review on these two areas. RECENT FINDINGS: The phenomenology research supports the notion of a discrete fatigue syndrome which can be distinguished from depression and anxiety. The current case definition, however, may need an improvement based on empirical data. Recent advances in understanding the pathophysiology of chronic fatigue syndrome continue to demonstrate the involvement of the central nervous system. Hyperserotonergic state and hypoactivity of the hypothalamic-pituitary-adrenal axis constitute other findings, but the question of whether these alterations are a cause or consequence of chronic fatigue syndrome still remains unanswered. Immune system involvement in the pathogenesis seems certain but the findings on the specific mechanisms are still inconsistent. Genetic studies provide some evidence of the syndrome being a partly genetic condition, but environmental effects seem to be still predominant and identification of specific genes is still at a very early stage. SUMMARY: The recent findings suggest that further research is needed in improving the current case definition; investigating overlaps and boundaries among various functional somatic syndromes; answering the question of whether the pathophysiologic findings are a cause or consequence; and elucidating the involvement of the central nervous system, immune system and genetic factors.

Analysis of anthrax and plague biowarfare vaccine interactions with human monocyte-derived dendritic cells.

The anti-biowarfare anthrax and plague vaccines require repeated dosing to achieve adequate protection. To test the hypothesis that this limited immunogenicity results from the nature of vaccine interactions with the host innate immune system, we investigated molecular and cellular interactions between vaccines, dendritic cells (DCs), and T cells and explored the potential for adjuvants (pertussis) to boost induction of host immunity. Human monocyte-derived DCs were matured in the presence of vaccines and analyzed for their ability to induce Th1/Th2 development from naive T cells, expression of cell surface maturation/costimulation molecules, and cytokine production. The vaccines showed different behavior patterns. Although the plague vaccine is equivalent to control maturation factors in maturation and stimulation of DCs and induces strong MLR and Th outgrowth, the anthrax vaccine is a poor inducer of DC maturation, as indicated by low levels of HLA-DR, CD86, and CD83 induction and minimal proinflammatory cytokine production. Interestingly, however, anthrax vaccine-treated DCs stimulate Th1 and Th2 outgrowth and a limited MLR response. There was no sustained negative modulatory effects of the anthrax vaccine on DCs, and its limited stimulatory effects could be overridden by coculture with pertussis. These results were supported by analysis of anthrax vaccine recall responses in subjects vaccinated using pertussis as an adjuvant, who demonstrate anthrax-specific effector T cell responses. These data show that the anthrax vaccine is a suboptimal DC stimulus that may in part explain the observation that it requires repeated administration in vivo and offer a rational basis for the use of complementary DC-maturing adjuvants in combined immunotherapy.

Cellular immune activation in Gulf War veterans.

The etiology and pathology of illnesses related to the first Persian Gulf War are unclear. Among the constellation of symptoms noted in sick veterans, some, such as skin rashes, musculoskeletal pains, and neuropsychiatric problems, have been proposed to reflect an underlying immune dysfunction. In this study we explored the hypothesis that sickness following deployment to the Gulf in 1991 is associated with altered immune function, and we examine possible associated exposures. In particular, we focused on peripheral blood Th1/Th2 balance by measuring intracellular production of IFN-gamma, IL-2 (Th1), IL-4 (Th2), and IL-10 by CD4 T cells, using a nested case control study design within a large epidemiological survey. We compared symptomatic Gulf War veterans (sGWV) with well GWVs (wGWV), and a second control group of symptomatic veterans who served in Bosnia or were nondeployed military personnel of the same era. We found evidence for an altered immune status in sGWV in comparison to the other study groups. In particular, ongoing Th1-type immune activation was associated with multisymptom illness in GWVs, with sick veterans having significantly elevated levels of IFN-gamma and IL-2 producing CD4+ cells in the absence of in vitro stimulation compared with wGWVs (P = 0.01 and P =0.001). In vitro polyclonal activation revealed significantly elevated levels of IL-10 producing memory CD4 cells in sGWVs (P <0.001), but other cytokines were normal. In terms of possible exposures that might influence immune function, we found a trend for reduced levels of IFN-gamma producing cells after polyclonal activation with increasing numbers of vaccines administered (P <0.05) but no changes in other cytokines. These data show that multisymptom illness in Gulf War veterans is characterized by ongoing Th1-type immune activation and a biased generation of memory cells secreting the suppressor cytokine, IL-10.