Complement in human disease

IWMUNOLOGY

TODAY

Complementin human disease Reinhard

Wikzner

and

Manfred

f! Dierich

signalling

from

outside

the cell, IS chemo-

ratm

tactic tar PMNs ~1 and inhibits N-formyl-methionyl-leucyl-phenylalanine (fMLP)-mediated iC5b67 instilled evoked PMN

C5a- and

superoxIde production. in the pleural cavity of mice migration without protein

leaks. of

A high-resolution map of the regulator complement activation (RCA) gene

cluster was introduced by D. Heine-Suiier (Madrid), based on 16 genetic markers and containing two new genes that ore not complement related. Interestingly, this map cleavage medt&ed

at adjacent differently

sites Cofactor action is depending upon the

Slk ot cleavage. Factor H not only promotes the decay of the C3 convertase of the alternative pathway (C3b,Bb) but also acts as a cofactor for factor l-mediated cleavage of C3b into iC3b. It has been proposed

shwn~

that

p‘ltwnts

wtl,

presented data systemic lupus

erythematosus (SLE) have Hugh levels of I& dwectt~d agamst the Cl‘, IWept”, (ClqR) AntKlqR i
Cr”41nktng

of F(ab), anti-ClqR,

bound to polvmorphonuclear (PivlN~), Induced an oxidatwe antKIqR se\‘errt\’

antlbodws of SLE

may

leukocytes burst. Thus, mfluence

tbc

that factor

H contains

B

E

R

,,I

‘401iilJ’i

1997

(Tel Aviv)

discussed

the differ.

crucml role m wgulation of the alternative pathway and in self/nonself-recognition. From studies of truncated and mutated fac-

based on sequence homology, antigenic crossreactivrty or functional similarity and lead to inhibition of the complemen

tor l-l proteins,

Park,

cascade,

proteolysis

Australia) suggested that the short consenSW rrpe.it (SCR) 20 contains the second heparm-binding site in factor H, and that

ponents,

release of complement

D. Gordon

(Bedford

factor H-related protein 3 but not 4 contams heparm-bindmg domains. On the basis of !!I results indicating

ultra

that

a potent

complement

inhibitory

anti-

body onpaxs both C5a liberation and terminal complement complex (TCC) assemblyS a humanized anti-C5 smgle-chain Fv has

not pxhclpate o

Infections 2. Fish&on

promising results trial (the antibody

from a is well

tolemtcd and has a long ha!f-life). A Nicholson-Weller (Boston, MA) reported on the IU two role of a TCC designatcd mactwe C5b67 (iC5b67). since it can-

T

cides with a region of loss of heterozygosity in breast cancer cells.

ent types of molecular mimicry of infectiour organism@, which can be described as eva. sion, subversion or exploitation. These an

antibody, and Phaw t climcal

c_

recombithat coin-

a binding site for polyanions such as heparin’ and that bindmg of factor H to he~~r1n/sialic-acid-rich surfaces plays a

been developed. S.A. Rollins (New Haven, CT) presented data on the inhibition of platclrt and leukocyte activation by this

o

also identifies a female-specific nation hot spot within the RCA

in lysis.

iC5b67

is active

m

of complement

corn

activator!

or capture of complement inhibitors. Bacterial meningitis IS characterized by : high mortality rate and persistent wurologi cal impairment. S.R. Barnum (Biwlingham AL) pointed out the necessity for rapid etio logi, .!I diagnosis and especially differenti ation between

bacterial

and aseptic

meningi

tis. Significantly increased levels of C3 am sactor B were found in the cerebrospina fluid of patients with bacterial but not vim meningitis, suggesting that quantitation o these proteins may diagnostic tool.

serve

as an importan

Many strains of group A Strcptocom h;.;,c been showo to bind to C4b-bindin; protem (C4BI’). The bacterial ligands ar members of the M protem family am hypervariability was evident when differ ent streptococcal proteins were compare{

/I iClh-iol9,“i,0!l?!

‘The 6th European hleetmg un Complement m Human Disease ~a, held at Innsbruck, Austria, on 12-15 March 1997.

;MMUNOLOGY

BOX (E Jchnsscn,

Lund)

Th15 mav

blologlcal Importance, ta rgets for the immune

mdlcate

espcclallv sy,lcm

thrlr

.7L1illd,OT

tg site on CD46 (membrar‘e sin, MCI’) mspplng to SARI

cofactor f7, but

pmthev

iffer in their apparent avldrty to CD-lb nder the intluence of SCR3+4. perhaps beause of subtle conformational difference\ a “d/or secondary interactmns (I’ yen). The virus receptor function 0

verlaps

with

Its complement

a Precise

l

l

l

l

l

l

l

function; l

l

A. Gruber (Innsbruck) prothat HIV-I is able to bind to via C5like regions on gp41

,nd CR5like regions E. Lukasser-Vogl

on Cn,tdirln. (Innsbruck)

disclosed

hat opsonized Cnudrrln trigger a selective elease of terminal complement protems 16 and C7 but not C8 nor C9 from PMNs. By xoviding C7, PMNs may enhance complr “ent attack locally

at inflammatory

sites.

One of the few virulence factor> associIted with severe malaria is the ability of Isttrodr~~ fnlcipnrr~~~~-infected eryt!;ro+:es o form rosettes with uninfected cells. .M. Moulds (Houston, TX) and co-workers dentified the involvement of CR1 in roseting and showed IRl-related jl(a-), which

that erythrocytes

with

the

Knops blood group variant has an increased frequency m

4fm-Americans, have a reduced ability to form rosettes. Thus, the increased frequency af this phenotype in Blacks may be due to :volutionnry

pressures.

HIV .md

AIDS

and

complement

protein elucldatrd the HIV and com-

plemeni, focusing on deleterious and benefv cial effec;s of complement activatio” by HIV and strategies developed by HIV to escqe complement-mediated lysls and to uhhze Its spreading and replicative activitf. G. Fust (Budapest) reported that the frequency (ClqAbs)

of comFIement

Involvement of complement m automlmune Beneficial and adverse effects of complement Use of complement regulatory protein Use of a”ticomp!ement

ant&dies

to inhibit

of autoantibodles agamst Clq was significantly higher I” \era of

Use of recombinant antagonists Use of gene-targeted

protems, disruption

pathxr,zvs

dehciencvzs t&n:: atlasi,

Y”W

disorders protein synthesis rn the bram tra”sge”lc animals for xenogcmc comF!exfnt

pt1ents as compared that the tttre\ decrea\ed

synthetic

\\lth ‘

scnhed the allotype speclficltv directed against Cl-mhlbltor patients parently,

ot antlbodlc5 (Cl-INW) 1”

with acquired anqo-~dern.~ these antlhodles arc rrstrlctcd

Ap to

the Val458 or Met45R allotyplc \ ar,an,\ of C:-INH. A new mutation of Clq dcflclencv has bcvn characterized by F Peby (klam/l and co-workers in a Momccan family a single base mutation I” the ClqB an~nc acid exchange (Gly6

gent led io an to Asp) ,~nd re-

sulted m the formatmn of II nonfunctlonal Clq of low molecular we& N. Rougler (Pans) reported ~1” J high prevalence of CJA among SLE patlents, gene delehons

and C4B dehucncles many ot them caused The

role

of C4A

ficiency and its sssocIahon with >pecltlc haplotypes m determnnng \usceptlblht\,

complement

(complement-knockout

the CD4’ cell count It ,vas pmpo~d th.lt de\~elopmmt of ClqAhs I”W bc due tl, a crossreaction between gpI20 and C lq M. Ciccardl (Mds”) and collogues dt,-

by

deficiencies G. Gras (Fontenay-au-Roses) multiple interactions between

charactenzahon

x!iv~t~c~:rxrzxbrmc

attack

5 frequently found m human immunoleficiency virus (HIV)-infected subjects, which is usuallv attributed to the Impalrrd ‘-cell immunity. ided evidence Yn!ufidn directly

in the field of complement at the meeting

srgnal transducnon

Interactions of complement with human ~mmunodeflciency Role of complement I” allergy, cancer and renal disease

l

Devaux, of CD46

molecular

I”clud:ng

Genetics of several complement components Diagnoshc aspects, zncludmg senslhve and specific bvxcmpatlbdlty M&x&r mechamsms of muoqqmsms to evade complement

l

Measles V”W\ and Its recomhln,~nt solble haemagglut”un share a common bmd-

I. Recent developments that were covered

0 Basic compiementology.

TOD-\f

d+ I ILA to

inh&xto:s ammals)

or receptor

for 1” xv

atudie%

IMMIJNOLOGY

ltdtr,ltl,w

TODAY

and Im k?lll

cIc“lr‘lIlcc

tttu tm, \\ It;> ci re~torrd p”‘!c’twn Ll 1 \V,llport (L”l;dm) dct.lllcd blamed 1”dCl

!\ith to

Clq

1~\pl”rc

,g tnv .,v,<*~,‘,t,“n iltil

we

hnockrxit

the

SLE More de\cloped

of lltlmon

E Lath (Bawl) reported that the rcriuchot? ot CR1 on human crythrocytcs I” auto-

rtwlt5

,tnn,~~ne dtwaws and AIDS do~\~nn~;;“latlot1 of synthesis ::” .::~::12t:::i; c>!ls. Hoacvcr,

m,~r

IllKla11:lT?‘LI

than high

Rcwn-

a* a

Il:x?‘.T!]

Cl‘,

dcflcwncy

d,fferenccs retlculocytc

halt “I tllc deflclent tltre% of antinuclear

nt,bodws. ajiamst sm$e-\trandcd DNA wttcular, compared wit11 lebh than ll)‘i; IIC control str.ms, and about 1 quarter

rn of of

,e dehctcnt wruloncphrltls

“,,CC dwd from severe gloTlw5, transgenlc animals

my pr”\ldc ~ath”g”le51’

17 \~aluable too1 to study the of aut”mlmunlty ssxwated

,ath complement

’ t Ulergy,

dehcwncy

anaphylatoxins

r heumatic disease PL Erdei (God) summarized

data on tlw role

of CD21

@X2),

epresentmg the cvtracellular domain of 11~ molecule, is spontaneously released ‘) hum.111 B and T cells, and c1rculateb 1 n serum m a complex together with C3 f ragmcnt~ and a trmwrr ( ID23 Tlus complex may

hypothesis. R.M. Goodfellow and colleagues (Cardif used soluble CR1 to treat rats with established

form of soluble exhibit a broad

Jury of experimental membrane nephritis.

explained.

renal

disease

and cancer The brain, as an immunologically

Neurological

w&&d

disease,

crllc

y:elded

different

results

tide. Thus, C3a and C5a affect distinct astrocytic cell receptors coupled to different signal transduction systems. Factor H-deficient pigs

develop

lethal

membr,,n”proliferati~,e glomerulonephritis type II wit11 a median survival of 31 days (J.H. Jsnsen, Oslo). Weekly transfusions of normal pig plasma to deficient pigs (!I= 27) resulted 10% of normal,

in a mean factor H level of and increased the survival

to 82 days. Less pronounced histological changes confirmed the delayed progression to glomerulonephritis by partial factor H van Dixhoorn

(Leiden)

that co-deposition of IgA lead to a more progressive In

reported

and IgG can course of IgA

an experimental

model

only the combined administration of l&2; and IgA anti-Thy 1.1 antibodies to Wista1 rats resulted in a complement-dependen synergistic renal inflammation. J. Hakulinen

(Helsinki)

and co-worken

theless, there IS growing evidence that complcment is involved in numerous brain

““ma cell Iins to study their increased se” sitivity to complement lysis upon blockadl of CD59, confirming earlier irt vifnr studies.

from complementSome of these also

express complement receptors (astmcyte+ express CRI, CR?, C5aR but not CR3); others are
plays

rl particular

role in de-

myelinattng diseases (multiple sclerosis, Gu~llam-Barr6 syndrome) and neuronal cell loss (Alzheimer’s disease). Glial cells (abtrocytcs) are even capable of synthcsiLml: all proteins required for the lytic cascade and also express a functwnal C3aR 11, r~rtm and 111human inflamed brains. In the brains

.

btit

cni:zrning membrane potential recordings. Hydrogen peroxide production WRS induced only by C5a and CSa-derived pep-

developed a microtomour spheroid mode of T47D breast cancer and PA-1 teratocarci

barrw or intmthecally producmg brain cells”.

1997

diS-

site, is physiologically sheltered from circolatmg cells and proteins of the blood. Never-

diseases”. B.l? Morgan (Cardif explained that complement in the central nervous systen1 may ortginate from a leaky blood-bran

,,‘a~, .11x, selected.

.

UMIIR

nephropathy.

(Hannow) and panned directly on C5aR’ cells This confmned postulated resrdues and revealed new bmdmg rwdues wtthm the effector domsln of C5a An antagomstic

:

ir.-

basement in a com-

I’~ck’s or Huntington’o

A. Isclw1k” (St l’ctcrsburg) reported tl1at C3a, C5.1 trl syn!hctic peptldes mcreased intracellular Ca” in human astrocytoma

(London)

I’MNs or m cells stably exfor elthcr human or mouse

.

glomerular

glomerular Deficiency

wtl1

edw, complement IS spontaneously activated by ncuron~ in the absence of antibodies

substitution. M.G.A.

system to study mteractwns between C5.7 and C5aR (Rrf 11). two CSa phage libraries were generated by j. Kohl and co-workers

mutant

1rtl1-

of patlent\

ponent of the classical pathway, such as C4, confers only partial protection, suggesting that both classical and alternative pathway mediate glumerular injury, as N.S. Sheerin

I I ~“!‘a! studx?, that sugt+stcd Ch and C4a I1ntcract tllrough t11c salw cellular receptor Uw>g a phage-dtspl.ly-b.,sed sclect~on

OCTOBER a.

antigen-induced

of acute antibody-mediated

&R This mdlcates that C:a does not nteract with C3aR. refutmg earher func-

Cia

mono-artrular

rttls, a recognized model for human synovitls. A flare followmg a rcpcated intraarhcular challenge was significantly dampened m the group that received soluble CR1

propertIes I ’ ange of mlmun”regulat”ry V Fr&naux-Bacchr I’-1.1~1 R5 Ames (Kmg of Prussia, PA) ~xplamrd that C4n. at concentrations up o 33 “I%,, had no effect on Ca” mobllizman m human xewng cDNAs

\aere found 11, the numbers of CR1 in patients wlth these

diw,rxs in comparison with normal patwnts, wh,ch excludes the reduced-synthesis

at the same time as the flare-inducing antigen. CJ-deticient mice are protected from functional and l1ist”l”gical manifestations

and

0 f the anaphylatoxms C3a and C5.1 “1 the focusmg on ., novel a ct,vat,on of ma\t cells, unction of C3a Its mhlbltory actwty on SE-med,ated tr~gpxmg of mucosal cells nterestmgly, tlu< functmn 15 not exhibited ty C5a (Ref 10) A soluble 135 kDa form

may be due to or degradation 1:” sigixhcarlt

Biocompatibility, transplantation

therapy

and

T.E. Mollnes (Rod”) gave an overview 01 complement as an indicator “t biomcom patlbility”. Assays based on nroepitope specific m”nocl”nal larly specific. TCC

antibodies are partico ElAs are more reliabl

than C% EIAs, a< CSa rapidly cellular receptor on leukocytes.

binds to Its However,

the sum of fluid-phase and surface-bound c5.1 correlates well wtll TCC fom,.!ti”n. Two pItfalls may OCLUT: (1) a chnical pitfall ‘no adverse effect5 observed, thus treatment is fme’;

and

(2) a biochemical

pitfall

-

IMMUNOLOGY’

TOGA,

estosterone (which, as Danazol, 15 used to ‘eat hereditary angio-oedema) doe5 not af-

Ilf.t!tlrt ,w HI/~‘LV~,

n transgenic mice. H.U. Lutz (Zurich) detailed that complenent attenuation by high-dose IgG appears D be a two-step process in systemic inflamnation.

High-dose

omplexes.

IgG

displaces

It then stimulates

Iennatomyositis, ration iIt oiro. R. Rieben

which (Leiden)

confirms

I11r:.lr1 r,,l;

I-

z Stcfan‘n.,,

I , Hare,.,.

proteins from the site of 5-50 times depending

m

IVICs

zompletely prevented ment in rat glomerun. J.R. Pratt (London)

at 600 mg

deposltion clarified

kg

Immunology

’

of cornpiethat the anh-

bition of complement

Therapeutic M. Westby

CR1 can

abrogate the induction of this response. This may improve prognosis for graft surviva1 in humans. E.H. Weiss (Munich) dctaled prehmmary data on attempts to generate transgenic mbbits using yeast arhfickl chromosomes expressing genes of the human RCA. So far only partial integrahons have hccn observed.

Conclusions Several hot spots of clinically r&ted complement research were apparent at the meeting.

in other

Adhesive interactions in the Cell Biology 7 (7). 289-295 Clinically

soluble

I1

Trends journals

HIV and chemokines: ligands sharing ceil-surface (I 997) Trends in Cell Biology 7 (7), 264-268

Dody response against major hlstocompatlhility complex class I in a kidney transplant IS dependent on complement and that inhlwith

L i\n.,,tr
IgM

{ated complement nflammation, by used.

//, 1..

inactithat

mrichment (70%) of intravenous immuno;!obulins (IVIGs) enhances C4h- and C3havenging activity, which removes acti-

the test

Llrll,,, r.111, 11, I,I,I./‘I *\r,., I I,,

References 7

nascent

their factor

reported

.\-box

effective

HIV-I

( 1997) Drug Discovery potential and A.G.

immune

system,

protease Thy

inhibitors, 2 (7), 261-272

receptws.

E-J. Brov~

J.P Vacca

P.R. Ciapham

(1997)

Trends in

and J.H.

of TNF-a inhibitors old and new, j.B. Marriot% Dalglelsn (I 997) Drug Disc&q T&q 2 ,?,273-282

The role of adhesion molecules in multiple sclerosis: biology, pathogenesis and therapeutic implications. J.J. Archelos and H-l? Hartung (I 997) Molecular Medicine Today 3 (7). 3 I f&32 I Phosphoinositide 3-kinases: a conserved family 6. Vanhaesebroeck. S.J. Leevers. G. Panayotou Trends in Biochemical Sciences 22 (7). 267-272

of signal transducers. and M.D. Waterfield -

(I 997)

Nitric oxide supplementation or synthesis block - which is the better approach co treatment of heart disease? M.J. Curtis and R. Pabla ( 1997) Trends in Pharmacological Sciences I8 (7). 239-244