Paschalis Sideras

The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases.

X-linked agammaglobulinaemia (XLA) is a human immunodeficiency caused by failure of pre-B cells in the bone marrow to develop into circulating mature B cells. A novel gene has been isolated which maps to the XLA locus, is expressed in B cells, and shows mutations in families with the disorder. The gene is a member of the src family of proto-oncogenes which encode protein-tyrosine kinases. This is, to our knowledge, the first evidence that mutations in a src-related gene are involved in human genetic disease.

Cloning of complementary DNA encoding T-cell replacing factor and identity with B-cell growth factor II

Proliferation and maturation of antigen-stimulated B cells are regulated by several soluble factors derived from macrophages and T cells1,2. These soluble factors are functionally divided into two groups: B-cell growth factor (BCGF), thought to be involved in B-cell proliferation; and B-cell differentiation factor (BCDF), responsible for maturation of activated B cells into immunoglobulin-secreting cells3–6. This classification needs to be re-examined in the light of the recent cloning of complementary DNA encoding IgG1 induction factor (interleukin-4, IL-4) from the 2.19 mouse T-cell line7. Recombinant IL-4 has BCGF and BCDF activities and affects B cells, T cells and mast cells (refs 7, 8; our unpublished data). Another well-characterized B-cell factor is T-cell replacing factor (TRF)9–12, which, when secreted by the murine T-cell hybridoma B151K12, is defined by two activities10–12: induction of IgM secretion by BCL1 leukaemic B-cell line; and induction of secondary anti-dinitrophenol (DNP) immunoglobulin G (IgG) synthesis in vitro by DNP-primed B cells. Although TRF from B151K12 was classified as BCDF, purified TRF has BCGF-II activity13. To elucidate the molecular properties of TRF we isolated cDNA encoding TRF from the 2.19 T-cell line and report here the structure and multiple activities of this lymphokine.

IgG1 induction factor: a single molecular entity with multiple biological functions.

A cDNA clone coding for the murine IgG1 induction factor has been isolated. The translation products directed by this clone were analyzed in different biological assays. The data obtained show that the IgG1 induction factor: Is involved in the regulation of IgG responses, by increasing IgG1 and decreasing IgG3 and IgG2b secretion; Induces hyper-Ia expression on resting B lymphocytes; Synergizes with anti-Ig in inducing DNA synthesis in resting B lymphocytes; Synergizes with DxS in inducing DNA synthesis by B lymphocytes; It induces DNA synthesis by either the T cell line CTL-L or Con-A blasts. Thus, this lymphokine in addition to IgG1 inducing activity has also BSF-1, BCGF-II and TCGF like activities. The fact that a single molecule can perform all the above listed functions has implications for our view of lymphocyte activation. It indicates that considering the B cell response as an ordered series of independently controlled events, is an oversimplified view of the dynamic process through which B cells are activated and also indicate the functional interconnection of the different elements of the immune system.

IgG1 Induction Factor

The IgG1 induction factor elevates the IgG1 response and reduces the IgG2b and IgG3 response in LPS-stimulated spleen cells. The factor is a lymphokine produced by T cells. The precursor frequency for cells secreting the IgG1 induction factor is at least tenfold lower as compared to those secreting interleukin 2. Some biochemical properties of the lymphokine are listed. The effects of gamma interferon in B cell-stimulated cultures are shown. Isolation of a cDNA clone coding for the IgG1 induction factor has been achieved and results of these studies are reviewed. Evidence is given that this lymphokine is the same as B cell stimulating factor 1, and we propose that it be renamed interleukin 4. Finally, the possible mechanisms of interleukin 4 are discussed.