CD5-positive B cells in rheumatoid arthritis and chronic lymphocytic leukemia

Immunology Today, vot 8, No 2, 7987

CD5-positiveB cells in rheumatoidarthritis and chroniclymphocyticleukmia Human B cells with receptors for rncuse erythro~.ytes (MER +) are present in small numbers in the blood and lymphoid organs of normal individuals ~,2. More recently, B cells expressing the T cell antigen-CD5, previously termed T1, have also been found in normal blood and lymphoid organs ~. This 67kDa molecule is equivalent to Ly i in the mouse ~ where it has been established that the B cells carrying this marker form a distinct lineage ~. The identification of normal human B cells expressing bo~h CD5 and MER3 suggests that these are overlapping if not identical cell populations. This is further supported by the fact that chronic lymphocytic leukaemic cells (CLL) of the B-cell type have been shown to be both CD5 and MER + (Ref. 1, 2, 6, 7 and 8). What then is the nature of this B cell population in normal individuals? It is found early in ontogeny 9,~° and large numbers of its cells appear in the circulation following bone marrow transplantation ~. The homologous mur ne B-cell population (Ly 1 +) is also. found early ~n development but in adult life the peritoneal cavity, rather than the bone-marrow is a major source of this population s, MER+/CD5 + B cells, like their murine counterparts, express mainly surface IgM and surface IgD (Ref. 2 and 10-12) and either ~ or X light chains (Ref. 11, 13 and Youinou etal., unpublished). Secondly, MER + B cells can respond to T-independent (Epstein-Barr virus) and also to T-dependent (pokeweed mitogen) polyclonal activators although only following activation with antiIgD antibody ~2,~,~. In addition, phorbol myristic acetate-induced activation of noimal B and CLL cells results in loss of MER (Ref. !6), ,;,hi!e thi~. treatment increases the expression of CD5 molecules in CLL and normal cells ~. That this B-cell population might represent a separate lineage observed at different stages of differentiation is supported by the murine studies in which the Ly 1 molecule is retained on all stages from pre-B cells through to antibody secreting cells s. Our hypothesis is that, like Ly 1 + murine B cells, CD5+/MER '~ B cells are a distinct B-cell lineage expressing immunoglobutin germ line genes coding for receptors for (non-organ specific) autoantigens and their anti-idiotypes. In their immature state, at least, these cell~ would be resistant to tolerization. Their specificities would include anti-Fc (rheumatoid factor) and anti-DNA antibodies. Our hypothesis is based on a number of observations which will now be discussed. In mice, Ly I÷B cells are the major population which give rise to IgM autoantibodies to bromelain-treated mouse erythrocytes and autoantibodies reactive with DNA and thymocytes in the autoimmune mouse strain NZB (Ref. 18). In addition, these cells spontaneously secrete IgM in these rr,ice ~8. Recent data from our laboratory and that of others have indicated an increase in CD5 + B cells (Ref 19 and Youinou etai., in press) and either a~ increase or decrease in MER + cells in the TDepartment of Immunology, Middlesex Hospital Medical School, London, and 2Department of Immunology, Univer_~i~, Hospital, Brest, France (c) 1987, F~I~,t,~,,(,t Sc,('nce Put)h'~b~r'~ H V , Am,,h,rdanl

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Peter M. Lydyard1, PierreY. Youinouz and AnneCooke circulation of rheumatoid art! ~fitis patients 2° - perhaps related to disease activity. In '..~, MER + 9 cells :3n be induced by Epstein-Barr virus to produce rheumatoid factor (RF) in vitro ~4. Immature 'conventional' B cells have immunoglobulin receptors which are easily modulated by anti-immunoglobulin 2~ and specific antigen 22, a property thought to be associated with central tolerance 2~, and it is interesting that human CD5 + B cells in the foetal spleen fail to cap their surface Ig (Ref. 23).

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Fig. 1. Interconnecting network of CD5",MER" B cells We hypothesize that the CD5" Immature B-ceil subset expresses germ-hne genes coding pnmanly for autoant~gens (e g Y) Inciud~n!] Idlotyp~c and antiid~olypic speof, cities and that these cells set up the reper'orre of the ~mmune system. They a/so react with 'external antigens' (eg X, cer'arn m~croorgan~sms) and form an inte'connectlng lalotypJc rTetwork wnlch is nc~rmallycontrolled by regulatory cells. Included in these speohc~tles are ant~bod,?s to Fc of IgG and DNA IgM. RF ~s produced as a normal consequence of at, immune response presumably through perturbation of :he i:tiotypic network ~ This response ,s normally reduced to basal levels again foll Jwing antigen stimulation However, detective suppre~,s~on of Fc-specihc CD5 o~lls ~;h;ch m~ght tn'.,o!vedifferent klr,ds of suppressor T cells (Ts) (ReL 39) would allow uncontrolled differentiation of these cells ~nto RF producing plasma cells following immune chalienge in rheumatoid arthntls (RA) On the other hand, malignant transformation of these cells would lead to expansion ot a clone of non-secretory B cells w~th the charactenst~c~of chronic lymphocytic leukemia (CLL) Intraclonal differentiation would glve r~seto some RF secreting cells. At the other end of the spectrum, mahgnant transformation of further different~, ted CDS' cells would result in Waldenstrom's Macroglobuhnaem,,J (W/vf) whe e n 3ny of the tumour cells are plasma cells In between RA and CLL would be the m~,ed essential cryoglobuhn,,em;a; (MO, where there appears to be a non.mah,_!nu~it monoclonal prehferatlon of F..-pruduung cells

37

Immunology Today, vol. 8, No. 2, 1987

38

This would suggest that CD5 ÷, MER + human and Ly 1 + murine B cells could be difficult to tolerize and would be potentially capable of synthesizing autoantibodies. Analysis of B-cell hybridomas derived from foetal and newborn mice have suggested that early B cells set up an ir, terconn,:cting network of idiotypes and antiidiotypes 24. Recent data has showr~ these early speclticitit s, probably encoded by germ-line genes, to contain a particular cross-read, we idiotype found on DNA autoantibod~es 2s. From these and other studies it seems likely that a subset of early B cells shows a high degree of connectivity and also reacts with a number of self antigens 26. We would imagine that this is the Ly 1+, CD5 + subset which appears early in ontogeny. It is interesting that monoclonal IgM spikes have been described in CD5 + CLL (Ref. 27) and in at least one case tnese antibodies had RF activity 28. Furthermore, in Waldenstrom's macrogiobulinaemia, many of the malignant lymphocytes have plasmacytoid features and secrete IgM. About 10% of the various monoclonal IgMs in these patients have rheumatoid activity 29 and one third have recently been shown to have anti-DNA activity 3°. In addition, the incidence of serum RF was greater in the first degree relatives of patients with B-cell lymphoproliferative diseases than in a control population 3~,32. During a normal immune response, RF (especially IgM) is produced 33 which may auc,ment the immune response. This enhancement may b.e through perturbation of the idiotype network 34 set up in the Ly 1 +, CD5 + set. Under normal circumstances this RF response is switched off and the level of RF return,; to a basal level. It is, however, possible to imagine th :bt defectnve regulation ot this response could lead to unde,~irable consequences. RF in patients with mixed cry(,globulinaemias 3s and rheumatoid arthritis 36 share common or cross-reactive idiotypes (CRI). Antibodies to idi,)types on RF are likely to regulate the in-vitro production of RF. Thus, defective suppression of CD5- cells carrying such a CRI could lead

1 Stathopoulos, G. and Elliot, E.V. (1984)Lancet, i, 600-601 2 Forbes, I.J. and Zalewski. P.D. (1976) Clin. Exp. Immu~7ol. 26, 99-107 Caligaris-Cappio, F., Gobbi, M. and Janossy, G. (1982)J. Exp. Med. 155, 623-628 4 Manohar, V., Brown, E., Leiserson, W.M. and Chused, T.M. (1982)J. Immunol. 129, 532-538 5 Hayakawa, K., Hardy, R.R., Herzenberg, L.A. and Herzenberg, L.A. (1985)J. Exp. IVied. 161, 1554-1568 6 Catovsky, D., Cherchi, M., Okos, A. etal. (1976)Br. J. Haematol. 33, 173-177 7 Wang, C.Y., Good, R.A., Ammirati, P. etal. (1980)J. Exp. Med. 151, 1539-1544 8 Martin, P.'., Hanson, J.A., Siadak, A.W. and Nowinski, R.C. (1981)J. ImmunoL 127, 1920-1923 9 Gupta, S., Pahwa, R., O'Reilly, R. etal. (1976) Proc. Natl Acad. 5ci. USA 73, 919-922 10 Bofil, M., Janossy, G., Janossa, M. etal. (1985)J. Immunol. 136, 1531-1538 11 Ault, K.A., Antin, J.H., Ginsberg, D. etal. (1985)J. Exp. IVied. 161, 1483-1502 12 Lucifero, G, Lawton, A.R. and Cooper, M.D. (1981) Cfin. Exp. Immunol. 45, 185-190 13 Poncet, P., Kocher, H.P., Pages,J. etal. (1985) Mol. Immunol. 22, 541-551 14 Fong, S., Vaughan, J.H. and Car~on, D.A. (1983)J. Immunol. 130, 162-164 15 Kuritani, T. and Cooper, M.D. (1982)J. Exp. Med. 155, 1561-1566 16 Forbes, I.J., Zalewski, P.D., Valente, L. and Murray, A.~. (]981) CancerLett. 14, 187-192 17 Miller, R.A. and Gralow, J. (1984)J. Immunol. 133,

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Fc-specific clones would lead to more damaging consequences. In this context, class switching from !gM tu IgG anti DNA has been shown to correlate with more severe kidney lesions in NZBxNZW mice 37. In addition, there are several observations where mcnoclonal immunoglobulins with anti-DNA specificities can also bind to the Fc of IgG (Ref. 38 and our own unpublished observations). In conclusion, we hypothesize that CD5 -~, MER + B cells represent a separate physiological B-celt population which, through a framework of self-reactivities, sets UlO the repertoire of the immune system. A hole in the idiotype network which results in lack of regulation of specific regulatory idigtypes carried by these particular B cells, together with other defects in suppressor cells 39 would give rise to expansion of autoreactive clones (see Fig. 1). A defect in regulation of certain CD5 + clones, by suppressor T cells for example, would result in the production of high levels of serum IgM RF in rheumatoid arthritis patients. On the other hand, malignant transformation of these cells may result in uncontrolled proliferation of RF-producing clones as seen in two ends of the spectrum of B-cell malignancies in CLL and in Waldenstrom's macroglobulinaemia. That IgM RF producing malignancies may be deri~ed from the CD5* subset has previously been postulated 4°. Furthermore, mixed essential cryoglobuliaemia; may represent a stage

of monoclonal proliferation without malignancy. This hypothesis offers a unifying scheme for lack of regulation of RF-producing clones in several diseases and suggests a number of testable predictions. Theauthorswouldliketo thankProfessorsI.M.Roittand G.Janossyfor helpful discussions. References

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18 Hayakawa, K., Hardy, R.R., Honda M. etal. (1984)Proc. Natl Acad. ScL USA 81, 2494-2498 19 Plater-zyberk, C., Maini, RN., Lam, K. etal. (1985)Arthritis Rheum. 28, 971-976 20 Youinou, P., Irving, W.L, Shipley, M. etal(198~.l Clin. Exp. Immunol. 55, 91-98 2! N~'sc_~!,G I V and Pike, B.L. (1935)Y. Exp. Med. 141, 904-917 22 Bruyns, C., Urbain-Versan~en, G., Planard, C. etal. (1976) Proc. NatlAcad. Sci. USA 73, 2462-2465 23 Antin, J.H., Emerson, S.G., Martin, P. etal. (1986) J. Immunol. 136, 505-510 24 Kearney, J.F. and Vakil, M. (1985)Ann. Inct. Pasteur Immunol. 137C, 77-82 25 Datta, S.K., Stollar B.D. and Schwartz, R.S. (1983)Proc. Nail Acad. 5ci. USA 80, 2723-2725 26 Holmberg, G.D. and Coutinho, A. (1986) Immunol. Today 6, 356-357 27 Deegan, M.J., Abraham, J.P., Sawdy, K.M. and van Slyck, E.J. (1984) Blood64, 1207-1211 28 Jirik, F.R., Sorge, J., Fong, S. etal. (1986)Proc. N~dAcad. ~(:i. USA 83, 2195-2199 29 Metzger, H. (1974)Adv. Immunol. 18, 169-207 30 Naparstek. Y., Duggan, D., Schattner, A. etal. (1985)J. Exp. Med. 161, 1525-1538 31 Seligmann, M., Danon, F., Mihaesco, C. and Fudenberg, H.H. (1967)Am. J. Med. 43, 66-83 32 Youinou, P., Le Goff, P., Saleun, J.P. etal. (1978) Biomedicine 28, 226-232 33 Tarkowski, A, Czerkinsky, C. and Nilsson, L.A. (1985) Clin.

Immunology Today, v~)l. 8, No. 2, 1987

Exp. Immunol. 61,379-387 34 Jerne, N.K. (1974)Ann. ImmunoL (Paris) 125C, 373-379 35 Kunkel, H.G., Pgnello, V., Joslin, F.G. and Capra, J.D. (1973)

J. Exp. Med. 137, 331-342

36 Forre, O., Dobloug, J.H.. Michaelsen, T.E. and Natvig, J.B. (1979) Scand. J. Iromunol. 9, 281-289 31 Steward, M.W. and Hay, F.C. (1976) Clin. Exp. Immunol. 26,

363-368 38 Rubin, R.L., Balderas, R.S.,Tan, E.M. etal. (1984) J. Exp. Mecl. 159, 1429-1440 39 Cooke, A., Lydyard, P.M. and Roitt, I.M. (1983)Immunol. Today4, 170-175 40 Seligmann, M. (1983)in Prog. Immunol V, pp. 1047-1051, Academic PressJapan, Inc.

I-E expression and susceptibility to parasite infecti0n In most inbred strains of mice, antigen-presenting cells express I-A and I-E antigens (class II major histocompatibility complex antigens), ,~nd these antigens are involved in antigenrecognition by T cells. In some strains I-E products are not expressed or aberrantly expressed, yet these mice seem to be immunologically normal.-In this article, Don Was~om and his colleagues discussreports that antigen presented in the context of I-E rJroducesa response which suppressesI-A restricted T-cell proliferation, in relation to their own findings that mice which do express I-E molecules are more susceptible to certain nematode infections than mice which do not express I-E. Genes within the I region of the mouse H-2 complex encode po!ypeptides which provide a context for recognition of antigen by T cells. Most inbred strains of mice express two I region products, I-A and I-E, on the surface of antigen-presenting cells. However, strains with the s, b, q or f haplotypes of H-2 fail to express the I-E product 1'2. Mice of the b and s haplotypes bear a deletion in the E:, gene, f haplotype mice synthesize predominantly an E, mRNA of aberrant size, and mice of the q haplotype seem to have a defect in R.NA _processing or a problem with rnRNA stability, or both~ Since mice which fail to express I-E are immunoiogically normal in most respects, the evolutionary significance of I-E expression remains a mystery. However, in several experimental systems investigators discovered that antigen presente, l to T cells in association with the I-E molecule induced a response which suppressed the c-'-:':" J f J l u L y of I-A-restricted T cells to proliferate in vitro 4,s. We were intrigued by these reports as they provide a mechanistic explanation for our observation that mice which express the I-E molecule are generally more susceptible to infc :tion with Trichinella spiralis and Nematospiroides dubius, two phylogenetically unrelated parasitic nematodes. Data from our studies, which are summar;zed below, suggest that a suboptimal antiparasite response occurs when relevant parasite antigens are i)resented to T cells in the context of the I-E molecule. The parasites The adult worms of Trichh~elia spira/is and Nemato'~piroio'es dubius are nematode parasites of the mouse sn,all intestine. Nematospiroides dubius is a parasite of v~"_'!

'Department of PathobiologicalSciences,Schoolof VeterinaryMedicine, Llniversi#yof Wisconsin-Madison,Madison, Wisconsin 53706, and 2Departmentof Immunology, Mayo Clinicand Mayo Foundation, Rochester,Minnesota55901, USA (~) 1987, [l'.~.vler Science Publishers B V , Am'derdam

OlOl ,19191871502O0

Donald L. Wassm Christopher J. Krco2, and Chella S. David2 mice, Mus musculus, and more than 25% of the wild mouse population may be infected. They acquire the infection by ingesting third stage (L3) larvae which have developed from eggs passed in the feces of a previously infected host. The ingested larvae undergo further development in the wall of the small intestine before emerging into the lumen of the qut where they live as adult worms. In the labolatory, all inbred strains of mice ate susceptible to initial infection with N. dubius. However, there are genetically controlled strain differences in ability to resist a challenge infection. Levels of resistance are determined by comparing the number of worms established in a challenge infection with those established in primary infection controls. Whde N. dubius parasitizes only rodents, T. spiralis infects most species of mammals. The adult worms of T. spiraiis live in the small intestine within a syncytium formed by rows of columnar epithelial cells. Because the worms live in direct contact with host cytoplasm they are said to be intramulticellular parasites. Adult female worms of T. spira/is give birth to living larvae which migrate from the gut, penetrate striated muscle cells, and develop intrace!!u!ar!y to the infective stage. Functional immunity against T. sp~ralis is expressed during primary as well as challenge infections by respenses which (I) expel worms from the gut, (2)limit the ability of adult female worms to reproduce, and (3) limit the abdity of newr~orn larvae to migrate from the gut and to penetrate striated muscle cells. Resistant strains of mice ~xpel worms from the gut quickly, and female worms taken from these mice are less fecund than worms from susceptible strains. Consequently, resistant strains of mice harbor approximately 50% fewer worms in their muscles than do susceptible strains. Such 50% reductions in worm burdens often fail to impress irnmunologists who are a.'-customed to studying the all-or-none, genetically controlled responsweness of inbred mice to antigens of fimited heterogeneity. However, the biological significance of these two-foid alfferences is pro,:.. found; depe,qding on I~evel~ of infection, such differences may distinguish between asymptomatic infections and serious disease or death. Because the mammalian immune system must certainly have evolved under selective pressures exerted by an array of antigenically complex

39