462 | JULY 2002 | VOLUME 2 www.nature.com/reviews/immunol

It is a well-known fact that the incidence ofautoimmune diseases is higher in females than inmales — systemic lupus erythematosus, forexample, occurs at a female-to-male ratio ofabout 10 to 1. The female sex hormone oestrogenis thought to be important for the pathogenesisof autoimmune diseases, but the molecular basisfor this has never been defined. In this study,Betty Diamond’s group shows that oestrogencan modulate the survival of immature B cells,leading to a more autoreactive B-cell repertoire.

Earlier work from this group in a mousemodel system established that the treatment ofnon-autoimmune mice that were transgenic forthe heavy chain of an anti-DNA antibody withoestradiol (E

2) led to the rescue of autoreactive

B cells that would normally have been deleted.The current study looked at changes in geneexpression in B cells that were treated with E

2 to

determine how this can result in a skewed B-cellrepertoire. Several E

2-upregulated genes were

identified in B cells, and four of the genes —encoding the CD22 receptor and the intracellu-lar tyrosine phosphatase SHP1 (both of which

can regulate the threshold for B-cell activation),the anti-apoptotic molecule Bcl-2 and theadhesion molecule VCAM1 — were chosen forfurther study.

Flow cytometry showed that receptors for E2

are expressed on B cells. Furthermore, the ectopicexpression of constitutively active E

2receptors on

B cells resulted in the increased expression ofCD22, SHP1 and Bcl-2. But, is there a functionalconsequence of increased expression of thesemolecules? To assess this, the team overexpressedCD22 or SHP1 in a B-lymphoma cell line tomimic the increased expression of these receptorsin E

2-treated B cells. Compared with mock-

transfected cells, the CD22- or SHP1-transfectedcells had decreased calcium-signalling responsesafter stimulation with mock antigen. This indi-cates that moderate changes in the level ofexpression of these molecules can alter B-cellsignalling and, so, might affect the tolerizationof autoreactive B cells.

Taken together, these results show that E2

can enhance the survival and activation ofautoreactive B cells, which might contribute tothe development of autoimmune disease.

Elaine Bell

References and linksORIGINAL RESEARCH PAPER Grimaldi, C. M., Cleary, J.,Dagtas, A. S., Moussai, D. & Diamond, B. Estrogen altersthresholds for B-cell apoptosis and activation. J. Clin. Invest. 109, 1625–1633 (2002)

Much of the recent work on the developmentof active, specific immunotherapy of cancerhas focused on the induction of CD8+

cytotoxic T-lymphocyte (CTL) responses,and several studies have shown that it ispossible to stimulate tumour-specific CTLsusing dendritic cells (DCs) that are loadedwith tumour antigens. But CD4+ T-helpertype 1 (T

H1) cells are also important

components of effective immune responses.In this study, Schuler–Thurner andcolleagues provide the first evidence that DCsthat are loaded with tumour-specific peptidescan rapidly induce T

H1 responses in cancer

patients that are readily detectable ex vivo.The DCs that were used for vaccination

in this study were derived from bloodmonocytes that were matured ex vivo usinga defined cocktail (consisting of interleukin(IL)-1β, IL-6, tumour-necrosis factor andprostaglandin E

2) and cryopreserved before

use. Aliquots of cells were thawed on the

day of vaccination and loaded with variousMHC class-I- and -II-restricted peptides.Patients with incurable melanoma weretreated with five biweekly vaccinations ofDCs, followed by assessment one monthafter the final vaccination.

The results showed that the vaccinationprotocol induced a rapid T

H1 response in

patients, both to a control immunizing antigenand also to defined MHC class-II-restrictedtumour antigens. Immune responses wereassessed on the basis of interferon-γproduction using ELISPOT assays andantigen-specific proliferative responses.

So, the results from this Phase I trial provideconvincing evidence that cryopreserved DCscan induce T

H1 responses against tumour

antigens without significant toxicity, and italso encourages further development ofDC-based vaccination technology.

Elaine BellReferences and links

ORIGINAL RESEARCH PAPER Schuler–Thurner, B. et al.Rapid induction of tumor-specific type 1 T helper cells inmetastatic melanoma patients by vaccination with mature,cryopreserved, peptide-loaded monocyte-deriveddendritic cells. J. Exp. Med. 195, 1279–1288 (2002) FURTHER READING Wolchok, J. D. & Livingston, P. O.Vaccines for melanoma: translating basic immunology intonew therapies. Lancet Oncol. 2, 205–211 (2001)

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