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Normal distribution of factor B (Bf) allotypes in multiple sclerosis
.I (1981) 137-140 FJielier/North-HolhmdBiomedicldPreis
JoiirtlaI of Neuwimmtmololy,
137
Short Communication Normal distribution of factor B (Bf) allotypes in multiple sclerosis J6rg Bertrams i Hans Grosse-Wilde 2 and Ernst K. Kuwert 2 t Ahteillmtlflie Labonltoruullimedi;m. St. Eh~ahelh Krankenhuai Essen and : Ins(liar/fir Virdogie und ImnmnoYogle, Ur~ivelsitT,r F_llel:,. (Gesamikochslhule). Esxen (F.R,G.)
(Received 18Augisi, 19~i0) (Acc~pled13O~t~ber, 1980(
smmry Bf allotyFes were determined in 200 mt'itiple sclerosis (MS) patients and compared to analogous control frequencies. No significant deviation of any B! phenotype was found. Also in HLA-BT- as w~ll as Dw2-positive patients normal Bf frequencies existed.
inu'mlucttea Like some other diseases with unknown aeliopathogencsis muhiple sclerosis (MS) is primarily associaled with H L A - D / D R , in the case of MS with Dw2 and DRY.
(Orosso-Wilde et al 1977; Tiwari el al. 1980). Using the concept of functionally interacting genes, mutant alleles of the complement gen¢ cluster C2, C4, Bf, being located in close neighborhood to HLA-DR on chromosome 6, might lead to altered immanologioal effe¢ior michanisms and increased diseas: susceptibility (gittoer and Beriranis 1981). Such a concept may be relevant for the manifestation of early onset insulin-depandent diabetes mallitus, which is p~silivaly associated with HLA-DR3 and DR4 (Berlrams et at. 1981b) and in iiddilkm tiith BfFI (Ikrtrams el al. 1979, 1981a), a rare gene product of the properdin lactor B system. Factor B plays an important role in C3 activation via the alternative pathway (Ritmer and Mauff 1978). Since differing results were obtained by our early analysis of Bf allotypes in 1(30 MS patients (Bertrams et al. 1977) and by Stewart et at. (1979), we typed another 100 patients for B( and HLA gen© products in order to analyse the Bf data of 200 MS patients.
~_.."7"~--~'d by I)iulidlt F o r l c h u l h l i f l , Grlnls Bt 7~8/I1-1V.Gr (308/11,~ Kll I$1/IV, Iteprini ~gltl~tl to: [~r. J0¢$ k r l r ~ Abl¢iluaI fflr LldbOlllOrlu/17irl. ~ l i b els!.. M ~ l ~ e l t r ~ 61, D-43K)0EMt.n I, F RG Ol65.~71s11110011-00110110l.$o ©
~,~ierlNo~h.l.lolhmdliio~dir~l pn~s
138 Material ~
Methods
Bf anotypes were determine¢l in 200 Caucasoid German MS patients with definite MS by immunofixation with specific antiscra to C3 activator protein (Behring-Werke, Marburg/Lahn, F.R.G.) after ele0trephoresis of the sera in agarose gel according to Alper et aL (1972). Typing for HLA-A, B, C antigens was carried out by a standard |~mphocyte microcytotoxicity techniqae (Mittal et al. 1968). HLA-Dw2 typing was performed by one-way mixed lymphocyte culture assay using Dw2-homozygous lymphocytes as stimulator cells (Grosse-Wilde et al. 1975). Control frequencies for HLA-A, 13, C and Bf alleles were taken from Bertrams and Baur (1979) and for Dw2 from Grosse-Wilde et aL (19"17). Results
The well known positive association of MS primarily with HLA-Dw2 and secondarily with HLA-B7 also exists in this material (Table I). The relative risk for Dw2 is 3.6 ( P < I 0 - 10) and for B7 it is 23 ( P = 3 X 10- 6 ). Bf phenotype frequencies of all 200 MS patients (a), however, showed no significant deviatiop from control f:cquer.t~ies, obtained by Bf typing of 536 healthy individuals (b) from the samo geographical area in Germany (Bertrams and Baur 1979). I n addition, the comparison of Bf phenotype frequencies of 79 HLA-B7-positive (c) as well as 9"/ HLA-Dw2-poshive MS patients (d) versus Bf control frequencies (b) yielded only insignificant differences. The decrease of the BfF phenotype frequency in HLA-BTpositive patienl:~ (24.1%) did not differ significantly from the increased frequency of BfF in HLA-Dw2-positive patiet~ts (34.0%). TABLE I PHENOTYPE FREQUENCIES(%) OF Bf ALLOTYPESAND OF HLA-B7AND Dw2 IN 2(]0:4S PzsTIENTSAND CONTROLS
HLA-B7
(a}
(t,)
(O
(d)
All MS (n = 200)
Controls (n = 536)
BT-pos. MS (n = 79)
Dw2-pos. MS (n = 97)
79 97 [48.5%)
el8 (22.1%)" 84/405 (20.7%) ** 92 (94.8%) 33
(39.~%)
HLA-Dw2 BIS BfF B[SO.?
awl * P = 3 x l 0 -~. "" P < IO-m.
[ ~,9
513
76
(94.S%) 61 (30.5%) 3
(95.7%] 1~3 (26.'/%) II
(96.2~) 19 (24.1~) [
lI.5~)
(Z.J~)
(L3~)
8 (4.0%)
10 (I.9%)
4 (5.1%)
(34.0~)
0 4 (4.1%)
139 l)~-tmkm O u r previous Bf typing results of 100 M S patients, which were not published in detail (Bertrams et al. 1977), showed no deviation from normal values. The present combined analysis o f 200 patients corroborates our results. The increasing BfS frequency as well as the significant increase of BfF homozygotes, observed by Stewart et al. (1979) in Austrafian MS patients, does not exist in our G e r m a n patients. These discrepancies may be explained by the pronounced population differences o f the Bf gene frequencies, which are most marked for the rare alleles BfFI and BfSO.7. These comparisons are between 2 Caue~-soid populations, which do, however, differ markedly in their gcographical latitude. Although ac¢ordin$ to our results no association with c o m m o n or rare Bf a:lot.vpes and Caucasoid G e r m a n MS patients could be found, the C2, C4, Bf linkag,, group may be o f significance for the pathogenesis o f MS. since an associatic:,, w k h decreased serum l o r d s o f C2 (Berirams et al. 1976, 19~0) and C4 (Zander et ~!. 1980) in relation to H L A - D w 2 / D R 2 could be demonstrate(I.
References Alper, C.A.. T. Boenisch and L Watson, Genetic polymorphism in human glyciue-rich bela-$1ycoproldn` J. Exp. Med.. 135 (1972) 68-80. Bertrams. ]. and M.P. Baur, HLA-A, B. Bf three point a,s.~ialion of 1072 haplotypes in a German population. Tissue Antigens. 14 (19")9) 317-324. lkrtran~ J., W. Opferkueh. ~J. Grosse-Wildc, W. Luboldt, W. Schuppien and E. Kuwert, C2 hypocomplemenmemia in multiple ~clei'~is, Lancet, ii (1975) 1358. Bertrams. J., H. Grosse-Wilde, P. WerneL W. Opfe~kueh. W. Schuppien w. Luboldt and E Kuwert, Histueompatibillty delenninants in multiple sclerosis, Tissue Antigens, 10 (1977) 190. Berlrams. J., P. Sodomann` D. GrDneklee and F.A. Gries, Bf in early-on.,e[ insulin-dependent diabeles, Lancet, fi (1979) 1240. Bcrtrams. J., M.P. Banr. D. GrOneklee and F.A. Gries, Age related a,~o~iation of insulin-dependent diabetes melti|us with Bn:l and the HLA-BI8, BfFI linkage ~oup, DilbctologJa. 1981a, In pt-ess. Bertran~ J., p. Sndormmn. F.A. Gties, B Sachs,~ and X. Jahnke. Die :ILA As.u-,ziationdes ic~ulinpflichtigen Typ I Diabetes mellitus. Di~sch.Med. Wschr.. 1981b. In pre-,s. Bertrand. $.. W. Opferkuc'h. H. Grosse-Wilde and EK. Kuv,zr,. HLA-I)w2 as~.,'ctated C2 hypOcolre plemenUietltiain multipk ~lerosis--A new genetic marker?. In: H.J. Bauer, S. Poser and G. Ritler (Eds.). Progre~ in M~tipl¢ Sclerosis Research. Sprlnger-Verlag,Berlin. Heldelb~rg, New York. 1980. pp. 476-484. Gro~ae-Wilde.H.. n. Nelzel, W. MempeL W. Ruppelt. G. Brehm. J. Bertrams. R. Ewald. V. Lenhard, RJltner. S. Scholz and ED. Albert. lmmunosee~ti~ of LD delerminanLsin men. In: F. Kissm~*erNli hen (Ed.), Histocompatlbillty Testing 1975, Munkspard. Copenhagen. 1975 pp. 526-532. Grof~-,WBd¢. H., J. Bert.rams. W. Schuppien, B. Nettel. W. Ruppell and E. Kuwert, HLA-D typing in 111 m u ~ k idermis pslknl$--Disttibution of 4 HLA-D alleles, Immunogenetics, 4 (1977) 481-48q. Mittal. K,4.. M.R. Mickey. D P. S/nlptland P.J. Tcnmtki, Serotypini for homouansplanlation, Putt 18 (Re'.im,went of miet'odropkt lymphocytowxJcity rot). Transplantation, 6 (1958) 913-920. Ritlllk~ Ch. lind J. Beflram~,On the sigltificm2ceof C2, C4 and faclor B polymo~phlsmsin disease, Hum. C,e~:t., 56 (1981) 235-247. R,itmer, Ch. ~ld G. ~'~luff, M t l C - ~ t e d complement itenes in man and animaJs. Beh~ng Inst. ~ I L . 62(978) 100-114. Stewart G.J.. A. ~ t e n and R.L. Kirk, $¢rorti linkage ~ir.cquilibnum between HLA-Dw2 and Bt~ in n~dt~ple sek,:Jrm~u d in the nomml populatio~ Titu~¢ Antiltem. 14 (i979) 8¢,-¢,'7. "[]wlt~ ~.L., ]q.E. Mo¢lon. J.M Lalouel. PJ. Terae4tkl.H. Zandero B.R. Hawkins atc~lY.W. Cho. M~dtipk ~lefo~t. In: P.l. Tems~d (Ed.). The Resents of the Univeerdtyof California, 1980. pp, 687-692.
140 Zander, H.. A. Aadre~, C. Ned. S Seholz. R. Wank and E.D. Albert. MtJlliple sclerosis(I~S)--Gcnotyp¢ anHysiso~ HI.A-A. B. C. D. a~d DR. Complement components C2, C3. C4. and Glyoxala,~¢ I (GLO) fram ~ibpair doublecak~ [Lmilies. In: Ptb~tra,:ts of the 4[h Inzematicnal Congress of Immunolo&y. Pal/s. 21-26 July 1980. Abstract No. 8.5.73.
Announcement Imerna,ionai Symposium an Thymus and Mya.slhenia Gratlis - Experience and Experimeres (Verona, Italy, 27-28 May. 198l) The Meeting is by invitation only. and is organized as formal lectures from invited speakers, and discussion with experts and audience. The official language is English and participation is free. hdormation can be obtained front Professor G. Trldente. Cattedra di Immunopatologla. Policlinico di Borgo Roma. 1-37100 Verona. Italy. Tel. (045) 912:S00/914.600. ext. 256 and 257.
JoiirtlaI of Neuwimmtmololy,
137
Short Communication Normal distribution of factor B (Bf) allotypes in multiple sclerosis J6rg Bertrams i Hans Grosse-Wilde 2 and Ernst K. Kuwert 2 t Ahteillmtlflie Labonltoruullimedi;m. St. Eh~ahelh Krankenhuai Essen and : Ins(liar/fir Virdogie und ImnmnoYogle, Ur~ivelsitT,r F_llel:,. (Gesamikochslhule). Esxen (F.R,G.)
(Received 18Augisi, 19~i0) (Acc~pled13O~t~ber, 1980(
smmry Bf allotyFes were determined in 200 mt'itiple sclerosis (MS) patients and compared to analogous control frequencies. No significant deviation of any B! phenotype was found. Also in HLA-BT- as w~ll as Dw2-positive patients normal Bf frequencies existed.
inu'mlucttea Like some other diseases with unknown aeliopathogencsis muhiple sclerosis (MS) is primarily associaled with H L A - D / D R , in the case of MS with Dw2 and DRY.
(Orosso-Wilde et al 1977; Tiwari el al. 1980). Using the concept of functionally interacting genes, mutant alleles of the complement gen¢ cluster C2, C4, Bf, being located in close neighborhood to HLA-DR on chromosome 6, might lead to altered immanologioal effe¢ior michanisms and increased diseas: susceptibility (gittoer and Beriranis 1981). Such a concept may be relevant for the manifestation of early onset insulin-depandent diabetes mallitus, which is p~silivaly associated with HLA-DR3 and DR4 (Berlrams et at. 1981b) and in iiddilkm tiith BfFI (Ikrtrams el al. 1979, 1981a), a rare gene product of the properdin lactor B system. Factor B plays an important role in C3 activation via the alternative pathway (Ritmer and Mauff 1978). Since differing results were obtained by our early analysis of Bf allotypes in 1(30 MS patients (Bertrams et al. 1977) and by Stewart et at. (1979), we typed another 100 patients for B( and HLA gen© products in order to analyse the Bf data of 200 MS patients.
~_.."7"~--~'d by I)iulidlt F o r l c h u l h l i f l , Grlnls Bt 7~8/I1-1V.Gr (308/11,~ Kll I$1/IV, Iteprini ~gltl~tl to: [~r. J0¢$ k r l r ~ Abl¢iluaI fflr LldbOlllOrlu/17irl. ~ l i b els!.. M ~ l ~ e l t r ~ 61, D-43K)0EMt.n I, F RG Ol65.~71s11110011-00110110l.$o ©
~,~ierlNo~h.l.lolhmdliio~dir~l pn~s
138 Material ~
Methods
Bf anotypes were determine¢l in 200 Caucasoid German MS patients with definite MS by immunofixation with specific antiscra to C3 activator protein (Behring-Werke, Marburg/Lahn, F.R.G.) after ele0trephoresis of the sera in agarose gel according to Alper et aL (1972). Typing for HLA-A, B, C antigens was carried out by a standard |~mphocyte microcytotoxicity techniqae (Mittal et al. 1968). HLA-Dw2 typing was performed by one-way mixed lymphocyte culture assay using Dw2-homozygous lymphocytes as stimulator cells (Grosse-Wilde et al. 1975). Control frequencies for HLA-A, 13, C and Bf alleles were taken from Bertrams and Baur (1979) and for Dw2 from Grosse-Wilde et aL (19"17). Results
The well known positive association of MS primarily with HLA-Dw2 and secondarily with HLA-B7 also exists in this material (Table I). The relative risk for Dw2 is 3.6 ( P < I 0 - 10) and for B7 it is 23 ( P = 3 X 10- 6 ). Bf phenotype frequencies of all 200 MS patients (a), however, showed no significant deviatiop from control f:cquer.t~ies, obtained by Bf typing of 536 healthy individuals (b) from the samo geographical area in Germany (Bertrams and Baur 1979). I n addition, the comparison of Bf phenotype frequencies of 79 HLA-B7-positive (c) as well as 9"/ HLA-Dw2-poshive MS patients (d) versus Bf control frequencies (b) yielded only insignificant differences. The decrease of the BfF phenotype frequency in HLA-BTpositive patienl:~ (24.1%) did not differ significantly from the increased frequency of BfF in HLA-Dw2-positive patiet~ts (34.0%). TABLE I PHENOTYPE FREQUENCIES(%) OF Bf ALLOTYPESAND OF HLA-B7AND Dw2 IN 2(]0:4S PzsTIENTSAND CONTROLS
HLA-B7
(a}
(t,)
(O
(d)
All MS (n = 200)
Controls (n = 536)
BT-pos. MS (n = 79)
Dw2-pos. MS (n = 97)
79 97 [48.5%)
el8 (22.1%)" 84/405 (20.7%) ** 92 (94.8%) 33
(39.~%)
HLA-Dw2 BIS BfF B[SO.?
awl * P = 3 x l 0 -~. "" P < IO-m.
[ ~,9
513
76
(94.S%) 61 (30.5%) 3
(95.7%] 1~3 (26.'/%) II
(96.2~) 19 (24.1~) [
lI.5~)
(Z.J~)
(L3~)
8 (4.0%)
10 (I.9%)
4 (5.1%)
(34.0~)
0 4 (4.1%)
139 l)~-tmkm O u r previous Bf typing results of 100 M S patients, which were not published in detail (Bertrams et al. 1977), showed no deviation from normal values. The present combined analysis o f 200 patients corroborates our results. The increasing BfS frequency as well as the significant increase of BfF homozygotes, observed by Stewart et al. (1979) in Austrafian MS patients, does not exist in our G e r m a n patients. These discrepancies may be explained by the pronounced population differences o f the Bf gene frequencies, which are most marked for the rare alleles BfFI and BfSO.7. These comparisons are between 2 Caue~-soid populations, which do, however, differ markedly in their gcographical latitude. Although ac¢ordin$ to our results no association with c o m m o n or rare Bf a:lot.vpes and Caucasoid G e r m a n MS patients could be found, the C2, C4, Bf linkag,, group may be o f significance for the pathogenesis o f MS. since an associatic:,, w k h decreased serum l o r d s o f C2 (Berirams et al. 1976, 19~0) and C4 (Zander et ~!. 1980) in relation to H L A - D w 2 / D R 2 could be demonstrate(I.
References Alper, C.A.. T. Boenisch and L Watson, Genetic polymorphism in human glyciue-rich bela-$1ycoproldn` J. Exp. Med.. 135 (1972) 68-80. Bertrams. ]. and M.P. Baur, HLA-A, B. Bf three point a,s.~ialion of 1072 haplotypes in a German population. Tissue Antigens. 14 (19")9) 317-324. lkrtran~ J., W. Opferkueh. ~J. Grosse-Wildc, W. Luboldt, W. Schuppien and E. Kuwert, C2 hypocomplemenmemia in multiple ~clei'~is, Lancet, ii (1975) 1358. Bertrams. J., H. Grosse-Wilde, P. WerneL W. Opfe~kueh. W. Schuppien w. Luboldt and E Kuwert, Histueompatibillty delenninants in multiple sclerosis, Tissue Antigens, 10 (1977) 190. Berlrams. J., P. Sodomann` D. GrDneklee and F.A. Gries, Bf in early-on.,e[ insulin-dependent diabeles, Lancet, fi (1979) 1240. Bcrtrams. J., M.P. Banr. D. GrOneklee and F.A. Gries, Age related a,~o~iation of insulin-dependent diabetes melti|us with Bn:l and the HLA-BI8, BfFI linkage ~oup, DilbctologJa. 1981a, In pt-ess. Bertran~ J., p. Sndormmn. F.A. Gties, B Sachs,~ and X. Jahnke. Die :ILA As.u-,ziationdes ic~ulinpflichtigen Typ I Diabetes mellitus. Di~sch.Med. Wschr.. 1981b. In pre-,s. Bertrand. $.. W. Opferkuc'h. H. Grosse-Wilde and EK. Kuv,zr,. HLA-I)w2 as~.,'ctated C2 hypOcolre plemenUietltiain multipk ~lerosis--A new genetic marker?. In: H.J. Bauer, S. Poser and G. Ritler (Eds.). Progre~ in M~tipl¢ Sclerosis Research. Sprlnger-Verlag,Berlin. Heldelb~rg, New York. 1980. pp. 476-484. Gro~ae-Wilde.H.. n. Nelzel, W. MempeL W. Ruppelt. G. Brehm. J. Bertrams. R. Ewald. V. Lenhard, RJltner. S. Scholz and ED. Albert. lmmunosee~ti~ of LD delerminanLsin men. In: F. Kissm~*erNli hen (Ed.), Histocompatlbillty Testing 1975, Munkspard. Copenhagen. 1975 pp. 526-532. Grof~-,WBd¢. H., J. Bert.rams. W. Schuppien, B. Nettel. W. Ruppell and E. Kuwert, HLA-D typing in 111 m u ~ k idermis pslknl$--Disttibution of 4 HLA-D alleles, Immunogenetics, 4 (1977) 481-48q. Mittal. K,4.. M.R. Mickey. D P. S/nlptland P.J. Tcnmtki, Serotypini for homouansplanlation, Putt 18 (Re'.im,went of miet'odropkt lymphocytowxJcity rot). Transplantation, 6 (1958) 913-920. Ritlllk~ Ch. lind J. Beflram~,On the sigltificm2ceof C2, C4 and faclor B polymo~phlsmsin disease, Hum. C,e~:t., 56 (1981) 235-247. R,itmer, Ch. ~ld G. ~'~luff, M t l C - ~ t e d complement itenes in man and animaJs. Beh~ng Inst. ~ I L . 62(978) 100-114. Stewart G.J.. A. ~ t e n and R.L. Kirk, $¢rorti linkage ~ir.cquilibnum between HLA-Dw2 and Bt~ in n~dt~ple sek,:Jrm~u d in the nomml populatio~ Titu~¢ Antiltem. 14 (i979) 8¢,-¢,'7. "[]wlt~ ~.L., ]q.E. Mo¢lon. J.M Lalouel. PJ. Terae4tkl.H. Zandero B.R. Hawkins atc~lY.W. Cho. M~dtipk ~lefo~t. In: P.l. Tems~d (Ed.). The Resents of the Univeerdtyof California, 1980. pp, 687-692.
140 Zander, H.. A. Aadre~, C. Ned. S Seholz. R. Wank and E.D. Albert. MtJlliple sclerosis(I~S)--Gcnotyp¢ anHysiso~ HI.A-A. B. C. D. a~d DR. Complement components C2, C3. C4. and Glyoxala,~¢ I (GLO) fram ~ibpair doublecak~ [Lmilies. In: Ptb~tra,:ts of the 4[h Inzematicnal Congress of Immunolo&y. Pal/s. 21-26 July 1980. Abstract No. 8.5.73.
Announcement Imerna,ionai Symposium an Thymus and Mya.slhenia Gratlis - Experience and Experimeres (Verona, Italy, 27-28 May. 198l) The Meeting is by invitation only. and is organized as formal lectures from invited speakers, and discussion with experts and audience. The official language is English and participation is free. hdormation can be obtained front Professor G. Trldente. Cattedra di Immunopatologla. Policlinico di Borgo Roma. 1-37100 Verona. Italy. Tel. (045) 912:S00/914.600. ext. 256 and 257.