It seems that for immunology, as in life in general, you don't know what you've got until it's gone. One of the best ways to appreciate the complexity of our immune defences is to look at the diseases that result when parts of the process are missing. On page 880, Charlotte Cunningham-Rundles and Prashant Ponda look at the immunodeficiency diseases that result from primary genetic defects in T- or B-cell responses. Not only can analysis of the genes that are involved teach us about the regulatory pathways for T and B cells, but it also offers the opportunity for early diagnosis and treatment of these life-threatening diseases.

Also in this issue, Charles Mackay and colleagues (page 853) discuss a recently identified population of T cells that is found in germinal centres; these cells are known as follicular B helper T (TFH) cells, and they are essential for the selection of high-affinity B cells. The discovery that the adaptor molecule SAP is expressed by TFH cells has provided a potential explanation for the human immunodeficiency disease X-linked lymphoproliferative syndrome (XLP), which results from mutation of the gene encoding SAP. Patients with XLP have a deficiency in B-cell responses, which might result from defective TFH-cell function.

Of course, one of the best-known and most clinically important immunodeficiency diseases of modern times is AIDS. On page 835, Anthony Fauci and colleagues discuss the role of natural killer (NK) cells in controlling HIV infection. Although NK cells can contribute to host immunity to HIV by lysing infected cells or preventing receptor-mediated virus entry, if infection progresses, then HIV viraemia can induce functional abnormalities in NK cells. An improved understanding of these effects could lead to novel therapies for HIV infection that promote the protective properties of NK cells.