Phagosome biogenesis, the process by which macrophages neutralize ingested pathogens and initiate antigen presentation, has entered the field of cellular mycobacteriology research largely owing to the discovery 30 years ago that phagosomes harboring mycobacteria are refractory to fusion with lysosomes. In the past decade, the use of molecular genetics and biology in different model systems to study phagosome biogenesis have made significant advances in understanding subtle mechanisms by which mycobacteria inhibit the maturation of its phagosome. Thus, we are beginning to appreciate the extent to which these pathogens are able to interfere with innate immune responses and manipulate defense mechanisms to enhance their survival within the human host cell. Here, we summarize current knowledge about phagosome maturation arrest in infected macrophages and the subsequent attenuation of the macrophage-initiated adaptive anti-mycobacterial immune defenses.

Multiple sclerosis is a complex disease and calls for integrated efforts from immunology, epidemiology, neuroscience and genetics. In particular, the immunological implications of environmental risk factors such as vitamin D desufficiency, smoking and Epstein-Barr virus infection need to be explored.

Due to somatic recombination and hypermutation, Ig variable heavy (V H ) and light (V L ) regions contain unique immunogenic determinants, idiotopes (Id), which can stimulate T cells. To address the relevance of this in a human disease, monoclonal IgG (mAb)-secreting B cell clones were established from the cerebrospinal fluid (CSF) of two patients with multiple sclerosis (MS). HLA-DR-restricted CD4 + T cell lines and clones from CSF of both patients specifically recognized autologous CSF mAb. The CSF T cell clones produced IFN-c; some also produced TNF-a, IL-10 and IL-5. V H and V L on the monoclonal IgG derived from CSF B cells expressed amino acid replacements due to somatic mutations. A T cell epitope was mapped to a V H framework region, where an amino acid replacement was critical for the T cell recognition. The finding of Id-specific T cells and Id-bearing B cells in the CSF indicates that they coexist within the diseased organ, and provide a basis for the study of Id-driven T-B cell collaboration in a human autoimmune disease.

The highly diversified variable regions of immunoglobulin (Ig) molecules contain immunogenic determinants denoted idiotopes. We have previously reported that T cells from multiple sclerosis (MS) patients recognize IgG from autologous cerebrospinal fluid (CSF), and mapped a T‐cell epitope to an IgG idiotope. To test the ability of CSF IgG molecules to elicit a broad polyclonal T‐cell response in MS, we have analysed T‐cell responses in the blood and CSF against idiotope peptides spanning complementarity determining region (CDR) 3 and somatic mutations within the variable regions of monoclonal CSF IgG. Consistent with a diversified idiotope‐specific T‐cell repertoire, CD4+ T cells from both patients recognized several idiotope peptides presented by HLA‐DR molecules. Mutations were critical for T‐cell recognition, as T cells specific for a mutated CDR1 peptide did not recognize corresponding germline‐encoded peptides. One T‐cell clone recognized both an idiotope peptide and the B‐cell clone expressing this idiotope, compatible with endogenous processing and presentation of this idiotope by B cells. These results suggest that mutated CSF IgG from MS patients carry several T‐cell epitopes, which could mediate intrathecal IgG production and inflammation in MS through idiotope‐driven T–B‐cell collaboration.