T-Cell Response to Antigen Important in CLL

[Guest guest]

HLA-DR ASSOCIATIONS AND CELL CONTACT IMPLICATE SPECIFIC T-CELL

RESPONSES IN THE PATHOGENESIS OF SPLENIC MARGINAL ZONE LYMPHOMA

110

Author Devereux, , LONDON, Kings College London United

Kingdom

Co-author(s) , Zadie , Bournemouth, Royal Bournemouth Hospital

Little, Ann-Margaret Dr, LONDON, Nolan Trust

Patten, Piers Dr, LONDON, Kings College London

Fowles, Finnuala , LONDON, Nolan Trust

s, Dr, LONDON, Kings College London

Oscier, Dr, Bournemouth, Royal Bournemouth Hospital

Background: There is now strong evidence that interactions between

the B-cell receptor (BCR) and antigen are central to the

pathogenesis of a number of chronic lymphoproliferative disorders

including B-cell chronic lymphocytic leukaemia (B-CLL) and splenic

marginal zone lymphoma (SMZL). Compared to normal B-cells, B-CLL

cells use a restricted range of immunoglobulin variable heavy chain

(Vh) genes which, along with other structural similarities, suggests

that these tumours arise from cells that have responded to a limited

number of antigens.

A particularly marked homology has been noted in the Vh3-21 subset

with a short conserved complementarity determining region 3 and

expression of the same Vlamba2-14 light chain strongly suggesting

recognition of a common antigen. Restricted Vh gene usage has also

been observed in SMZL; for example in one series, Vh1-02 expression

was reported in 18/40 cases.

In addition to signals through the BCR, there is also evidence that

T-cell costimulation plays a role in the pathogenesis of many low

grade lymphomas. In gastric marginal zone lymphoma for example, T-

cell responses to Helicobacter pylori derived peptides provide

signals that sustain the developing B-cell tumour and responses to

autoantigens and other infectious organisms have been implicated in

extranodal lymphomas at other sites. In B-CLL, activated CD40L+ T-

cells neighbour proliferating leukaemic cells in so called

pseudofollicles within the bone marrow and lymph nodes and, although

the reason for their presence is unclear, it is suggested that they

play a key role in the tumour microenvoronment.

Aims: To investigate whether antigen specific T-cell responses

promote the progression of B-CLL and SMZL.

Methods: HLA typing was performed on subsets of B-CLL and SMZL and a

group of 1667 normal controls. Sections of SMZL spleen were analysed

by multiparameter confocal immunofluorescence microcopy.

Results: Of 36 patients with SMZL, 30 (83%) expressed either HLA-

DR15, HLA-DR4 or both compared to only 931 (56%) of the normal

controls (p=0.001). The significance of this association was

maintained when corrected for the analysis of multiple HLA-DR

alleles (corrected p=0.013). Surprisingly, the nature of the HLA-DR

association was dependent on the Vh gene utilised by the tumour. Of

the 18 cases of Vh1-02 SMZL, 11 (61%) expressed HLA-DR15 compared to

26% of normal controls (p=0.0022, corrected p=0.029) whilst 13 (72%)

of the 18 non Vh1-02 cases expressed HLA-DR4 compared to 36% of the

controls (p=0.0023, corrected p=0.03). An excess of HLA-DR4

expression was also observed in patients with Vh1-02 SMZL that did

not express HLA-DR15 (71% vs 19% of controls, p=0.015). No clear

association between any of the subgroups of B-CLL and HLA type was

observed. Analysis of SMZL spleen showed that proliferating tumour

cells frequently contact T lymphocytes whereas non-proliferating

cells do not (Figure 1. T-cells red, B-cells green, Ki67 white).

Conclusion: Taken together these results suggest that a specific T-

cell response to antigen plays a role in the pathogenesis of this B-

cell disorder. The observation that the Vh gene used by the tumour

specifies the type of HLA restriction implies that the BCR and

costimulatory T-cells respond to the same antigen.