Lupus (1998) 7, 280 ± 284

ß 1998 Stockton Press. All rights reserved 0961-2033/98 $12.00

http://www.stockton-press.co.uk/lup

REVIEW

Pathogenesis of vasculitis
CGM Kallenberg and P Heeringa
Department of Clinical Immunology, University Hospital Groningen, The Netherlands

This review discusses current thoughts on the pathogenesis of vasculitis. Secondary vasculitides,
frequently associated with infections or systemic autoimmune diseases, are, in most cases,
characterized by immune deposits in the vessel wall, which probably underlies the development of
lesions. In the primary vasculitides, immune deposits are generally absent. A group of primary
vasculitides is, however, strongly associated with anti-neutrophil cytoplasmic autoantibodies
(ANCA). Various in vitro and in vivo experimental data suggest that those ANCA are involved in
the pathogenesis of lesions in the associated disorders.

Keywords: systemic vasculitis; anti-neutrophil cytoplasmic antibodies; Wegener's granulomato-

sis; pathophysiology

Introduction secondary vasculitides will be brie¯y discussed. The

The systemic vasculitides comprise a diverse group of
disorders characterized by in¯ammation of the blood
vessel wall. The localization and size of the in¯amed
vessels and the nature of the in¯ammatory process, as
well as its systemic effects, determine the clinical
presentation of the disorder.
Vasculitis may, incidentally, result from direct
invasion of the blood vessel wall by micro-organisms
or from microbial embolization.1 Many cases of
vasculitis are secondary to other diseases. These
secondary vasculitides are frequently characterized by
immune complex deposition, as will be discussed later
on. In the remainder of cases in which vasculitis
is histopathologically demonstrable, no underlying
disorder or direct infection of the vessel wall can be
detected. Those primary or idiopathic vasculitides
constitute a heterogeneous group of disorders that are
classi®ed based on the size of the vessels involved, the
histopathological ®ndings and the clinical symptoms
(Table 1).2 ± 4 The pathogenesis of the primary
vasculitides is far from understood, but recent
developments have shed some light on the patho-
physiological processes underlying those disorders.
In this review the pathogenetic pathways in the
Correspondence: Prof.dr. CGM Kallenberg, Department of Clinical
Immunology, University Hospital, Hanzeplein 1, 9713 GZ Groningen,
The Netherlands.
main focus will, however, be on recent studies on the
pathogenesis of the primary vasculitides.
Secondary vasculitides
As stated before, many cases of secondary vasculitis
demonstrate immune deposits within the vessel wall
by direct immuno¯uorescence. A classical example is
the occurrence of leucocytoclastic vasculitis, clini-
cally apparent as purpura, in patients with cryoglobu-
linemia as part of Sjùgren's syndrome. Cryoglobulins
composed of monoclonal rheumatoid factor and
polyclonal immunoglobulin G are deposited in the
vessel wall and activate the complement cascade
along the classical pathway. Neutrophils are attracted
and activated, and invade the vessel wall resulting
in leucocytoclastic vasculitis. Activation of the
complement cascade with consumption of com-
plement components is demonstrable by decreased
levels of complement C3 and C4 and increased levels
of C3d, a breakdown product of C3 after activation. In
addition, circulating immune complexes can be
detected in serum.
Immune complex-mediated vasculitis has been
suggested to occur in association with systemic
autoimmune diseases and infections.5 In the systemic
autoimmune diseases, particularly systemic lupus
erythematosus (SLE), nuclear antigens and their
corresponding antibodies have been thought to be

Downloaded from lup.sagepub.com at Bobst Library, New York University on June 4, 2015

CGM Kallenberg and P Heeringa
Table 1 Classi®cation of primary vasculitides according to the
Chapel Hill Consensus Conference
Large vessel vasculitis
Giant cell (temporal) arteritis
Takayasu arteritis
Medium sized vessel vasculitis
Polyarteritis nodosa
Kawasaki disease
Small vessel vasculitis
Wegener's granulomatosisa
Churg ± Strauss syndromea
Microscopic polyangiitisa
SchoÈnlein ± Henoch purpura
Essential cryoglobulinemia vasculitis
Cutaneous leukocytoclastic angiitis
a
Strongly associated with anti-neutrophil cytoplasmic antibodies (adapted
from Ref. 3).
pathogenetically involved. Recent ®ndings do, how-
ever, support an (additional) mechanism in which the
antigen is ®rst planted in the vessel wall. Binding of
nucleohistones to the (glomerular) basement mem-
brane in lupus nephritis, due to charge interaction, is
followed by binding of antibodies.6 This in situ
immune complex formation may be operative in
many cases of immune complex-mediated vasculitis.
Besides systemic autoimmune diseases, infections
are associated with vasculitis. Bacterial and viral
infections may induce the formation of immune
complexes consisting of microbial antigens and their
corresponding antibodies which, either by deposition
from the circulation or by in situ formation, results in
vasculitides. The association of cryoglobulinemia with,
particularly, hepatitis C virus (HCV)7,8 is remarkable in
this respect. Different mechanisms may, however, be
operative. First, microbes may directly invade the
vessel wall followed by an infectious in¯ammatory
process.1 Secondly, certain viruses, such as cytomega-
lovirus, can penetrate endothelial cells and activate
those cells leading, along pathways that still have to be
explored, to vasculitis.8 Thirdly, bacterial antigens from
Staphylococci, such as Staphylococcal neutral phos-
phatase, can attach to basement membranes and bind
Pathogenesis of vasculitis
281
IgG non-speci®cally,9 also resulting in immune com-
plex formation. Thus, microbial agents are de®nitely
involved in the etiopathogenesis of vasculitis. The
precise pathophysiology of the associated secondary
vasculitides is still under study. Also, in other forms of
secondary vasculitis, for example, drug-related, the
exact pathophysiological mechanisms have not been
fully elucidated.
Primary vasculitides
In classical polyarteritis nodosa (PAN) viral infections
seem to be involved in some 20% of cases.8 Hepatitis
B virus (HBV) and HCV, as well as HIV and,
possibly, parvovirus, have been thought to be causally
related to the development of PAN in these cases. The
pathophysiological mechanisms are only partly under-
stood, as discussed in the previous section. As
mentioned before, HBV-, HCV-, and HIV-infection
are in many more cases associated with mixed
cryoglobulinemic vasculitis.7,8 How those viruses
induce cryoglobulins is still open for study.
In the majority of cases with primary vasculitis,
exogenous factors are not directly demonstrable.
There is increasing evidence that autoimmune re-
sponses are operative in those disorders. Although the
possible pathogenic role of anti-endothelial cell
antibodies and the anti-phospholipid antibodies in
systemic vasculitis (reviewed in Ref. 10) should be
mentioned, the focus has been on anti-neutrophil
cytoplasmic antibodies in recent years.
Anti-neutrophil cytoplasmic antibodies
(ANCA) and the pathophysiology of systemic
vasculitis
As shown in Table 1, Wegener's granulomatosis
(WG), microscopic polyangiitis (MPA), Churg

Table 2 Pathogenic effects of anti-neutrophil cytoplasmic antibodies (ANCA) as derived from in vitro studies
1. Activation of neutrophils primed with low dose TNFa resulting in the production of reactive oxygen intermediates (ROI) and the release of lysosomal
enzymes.13 This process only occurs when neutrophils are allowed to adhere to a surface; this adherence particularly involves the b2-integrins.14
Priming (and apoptosis) results in expression of the target antigens of ANCA on the cell surface making them accessible for ANCA.15;16
Neutrophil activation by ANCA is also dependent, probably, on the interaction of the Fc-part of ANCA with, particularly, the FcgRIIa-receptor on
neutrophils.17
ANCA-induced ROI production and degranulation is enhanced in the presence of extracellular arachidonic acid.18
2. Activation of the 5-lipoxygenase pathway in neutrophils inducing the production of large amounts of leukotriene B4, a potent chemo-attractant for
neutrophils.18
3. Induction of cytokine production such as IL-1b by neutrophils.19
4. Induction of the production of ROI20 and monocyte chemo-attractant protein-1,21 by monocytes.
5. Lysis of endothelial cells previously incubated with myeloperoxidase (MPO) or proteinase 3 (Pr3).22,23
Upregulation of adhesion molecules on (primed) endothelial cells.24
Lysis of (primed) endothelial cells in the presence of neutrophils.25
6. Interference with the inactivation of Pr3 by a1-antitrypsin26 which may result in persistently active Pr3.

Downloaded from lup.sagepub.com at Bobst Library, New York University on June 4, 2015
 Pathogenesis of vasculitis
CGM Kallenberg and P Heeringa
282
Strauss Syndrome (CSS) and idiopathic necrotizing

Pauci-immune character disputed by

Pre-treatment with antibiotics gives
crescentic glomerulonephritis (NCGN) are closely

Selective breeding for crescent

Scanty immune deposits in the
associated with autoantibodies to either proteinase 3

Anti-anti-idiotypic responses
severe reduction of lesions
(Pr3) or myeloperoxidase (MPO).11 Changes in titers

No lesions in the kidneys

Remarks
of those autoantibodies seem to re¯ect changes in
disease activity.12 Those ®ndings suggest that the
autoantibodies are involved in the pathophysiology of
the associated disorders. Experimental evidence for

formation

others36
the pathogenic potential of ANCA has been derived

kidney
mainly from in vitro studies. Those studies are
summarized in Table 2. One may conclude from
those studies, that ANCA are able to aggravate a

Pauci-immune necrotizing crescentic

subclinical in¯ammatory process by activating, along

Small vessel vasculitis in the gut,

Systemic vasculitis (kidney, gall

glomerulonephritis, vasculitis in

Sterile micro-abscesses in lungs

several lines, neutrophils and monocytes. In addition,

in¯ammatory changes in many

bladder), lymphoproliferation
endothelial cells are potentially a target of ANCA,

Vasculitis in lungs and gut

Pauci-immune crescentic
either indirectly via endothelial binding of Pr3=MPO

Lesions
released from neutrophils, to which the antibodies can

glomerulonephritis
bind, or directly by reacting with Pr3 expressed on the
surface of endothelial cells as demonstrated by Mayet

other organs
Table 3 Animal models of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis/glomerulonephritis
et al,27 but disputed by others.28

organs
Although all of the aforementioned data suggest
that ANCA are pathogenic, more direct proof
should come from in vivo studies on exper-

Multiple autoantibodies, polyreactive

imental animals. Until now, a fully satisfactory

Amongst others, autoantibodies to

with MPO, DNA, lactoferrin, etc.
animal model for ANCA-associated vasculitis has

Mouse antibodies to human Pr3

Anti-MPO as part of polyclonal
Autoantibody response

cross-reacting with rat MPO

cross-reacting with rat MPO

not been developed. Nevertheless, several in vivo

Antibodies to human MPO

Antibodies to human MPO

models are presently available that support a patho-
autoantibody responses

genic role for ANCA,29 summarized in Table 3. In

certain models,30 ± 34 vasculitis and=or crescentic
glomerulonephritis develops spontaneously in con-
junction with autoantibodies to MPO. The autoanti-
body response to MPO is, however, part of a more
MPO

polyclonal autoantibody response which does not

allow the analysis of the speci®c contribution of anti-
MPO to the development of vasculitis. The anti-anti- Immunization with human anti-Pr3
Immunization with human MPO,

Immunization with human MPO,

systemic injection of products of
products of activated neutrophils
ex vivo perfusion of kidney with
Injection with mercuric chloride

idiotypic model38 for anti-Pr3 is interesting but awaits

con®rmation as well as further analysis of the lesions.
It is important to mention that induction of ANCA
Induction

activated neutrophils

(anti-MPO) alone does not result in lesions.35 ± 37

When, however, products of activated neutrophils
are present in the circulation, pauci-immune crescen-
Spontaneous

Spontaneous

tic glomerulonephritis35 and systemic vasculitis37 can

develop.
MPO ˆ myeloperoxidase; Pr3 ˆ proteinase 3.

All of the aforementioned in vitro and in vivo

experimental data lead to the conclusion that ANCA
Brown-Norway rat

Brown-Norway rat

Brown-Norway rat

in combination with exogenous factor(s) that induce

MRL=lpr mouse
Animal strain

pre-activation (priming) of neutrophils, may result in

Balb-c mouse
SCG mouse

systemic vasculitis and glomerulonephritis. The

exogenous factors have not yet been de®ned, but the
observations that carriage of Staphylococcus aureus
is an important risk factor for relapses in WG39
and that maintenance treatment with trimethoprim=
Various31 ± 33
30

Heeringa37
Brouwer35
Mathieson

sulfamethoxazole prevents relapses40 suggest that

34

Blank38
Author

Kinjoh

microbial factors are also involved in the primary

vasculitides.

Downloaded from lup.sagepub.com at Bobst Library, New York University on June 4, 2015

CGM Kallenberg and P Heeringa
T-lymphocytes in the systemic vasculitides
Whereas many experimental and clinical data are
available on the role of autoantibodies in systemic
vasculitis, the role of T-cells has been explored to a
limited extent only. In the ANCA-associated vasculi-
tides T-cell responses of peripheral blood mono-
nuclear cells to Pr3 but hardly to MPO have been
documented in patients but also, albeit to a lesser
extent, in healthy controls.41 The functional character-
istics of those cells, the epitopes involved, and the
analysis of tissue in®ltrating lymphocytes, are still
open to study. More interestingly, skewing of the T-
cell repertoire due to preferential use of certain Vb
genes have been noted in a number of vasculitides,
notably in Kawasaki disease,42 microscopic polyan-
giitis,43 and, very recently, in WG.44 These data can be
consistent with antigen or superantigen, particularly
staphylococcal superantigen, stimulation. It should,
however, be kept in mind that shaping of the
peripheral blood T-cell repertoire, also occurs with
increasing age.45 Certainly, more work should be done
on T-cells in systemic vasculitis. In this respect, the
studies of Weyand and Goronzy46 on T-cell macro-
phage interactions in the vessel wall of giant cell
arteritis are promising.
Conclusion
The etiopathogenesis of the primary systemic vasculi-
tides has not yet been clari®ed in detail. The detection
of anti-neutrophil cytoplasmic antibodies in a number
of those diseases has, however, given a huge impulse
to the unraveling of pathogenetic pathways operative
in the vasculitides. In addition, further analysis of the
speci®c immune responses underlying the idiopathic
vasculitides may bene®t from recent developments in
molecular immunology.
References
1 Somer T, Finegold SM. Vasculitides associated with infections,
immunization and antimicrobial drugs. Clin Inf Dis 1995; 20: 1010 ±
1036.
2 Hunder GG et al. The American College of Rheumatology 1990
criteria for the classi®cation of vasculitis. Arthritis Rheum 1990; 33:
1065 ± 1067.
3 Jennette JC et al. Nomenclature of systemic vasculitides: the proposal
of an international consensus conference. Arthritis Rheum 1994; 37:
187 ± 192.
4 Lie JT. Nomenclature and classi®cation of vasculitis: plus cËa change,
plus c'est la meÃme chose. Arthritis Rheum 1994; 37: 181 ± 186.
5 Theo®lopoulos AN, Dixon FJ. Immune complexes in human diseases.
Am J Pathol 1980; 100: 530 ± 594.
6 Bruggen MCJ van, Berden JHM. Central role for nucleosomes in
lupus. Nephrol Dial Transplant 1996; 11: 1219 ± 1222.
Downloaded from lup.sagepub.com at Bobst Library, New York University on June 4, 2015
Pathogenesis of vasculitis
283
7 Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus infection in
type II cryoglobulinemia. N Engl J Med 1992; 327: 1490 ± 1495.
8 Guillevin L, Lhote F, Gherardi R. The spectrum and treatment of virus-
associated vasculitides. Curr Op Rheumatol 1997; 9: 31 ± 36.
9 Yousif Y et al. Staphylococcal neutral phosphatase. A highly cationic
molecule with binding properties for immunoglobulin. APMIS 1991;
102: 897 ± 900.
10 Kallenberg CGM. Laboratory ®ndings in the vasculitides. Bailliere's
Clin Rheumatol 1997; 11: 395 ± 421.
11 Kallenberg CGM, Brouwer E, Weening JJ, Cohen Tervaert JW. Anti-
neutrophil cytoplasmic antibodies: current diagnostic and pathophy-
siological potential. Kidney Int 1994; 46: 1 ± 15.
12 Cohen Tervaert JW, Stegeman CA, Kallenberg CGM. Serial ANCA
testing is useful in monitoring disease activity of patients with ANCA-
associated vasculitides. Sarcoidosis 1996; 13: 241 ± 245.
13 Falk RJ, Terrell RS, Charles LA, Jennette JC. Anti-neutrophil cytoplasmic
autoantibodies induce neutrophils to degranulate and produce oxygen
radicals in vitro. Proc Natl Acad Sci 1990; 87: 4115 ± 4119.
14 Reumaux D, Vossebeld PJM, Roos D, Verhoeven AJ. Effects of tumor
necrosis factor-induced integrin activation on Fcg receptor II-mediated
signal transduction: relevance for activation of neutrophils by anti-
proteinase 3 or anti-myeloperoxidase antibodies. Blood 1995; 86:
3189 ± 3195.
15 Csernok E et al. Activated neutrophils express proteinase 3 on their
plasma membrane in vitro and in vivo. Clin Exp Immunol 1994; 95:
244 ± 250.
16 Gilligan HM et al. Antineutrophil cytoplasmic autoantibodies interact
with primary granule constituents on the surface of apoptotic
neutrophils in the absence of neutrophil priming. J Exp Med 1996;
184: 2231 ± 2241.
17 Mulder AHL et al. Activation of granulocytes by anti-neutrophil
cytoplasmic antibodies (ANCA); a FcgRII-dependent process. Clin
Exp Immunol 1994; 78: 270 ± 278.
18 Grimminger F et al. Neutrophil activation by anti-proteinase 3
antibodies in Wegener's Granulomatosis: Role of exogenous arachi-
donic acid and leukotriene B4 generation. J Exp Med 1996; 184:
1567 ± 1572.
19 Brooks CJ et al. IL-1b production by human polymorpho-
nuclear leukocytes stimulated by anti-neutrophil cytoplasmic autoanti-
bodies: relevance to systemic vasculitis. Clin Exp Immunol 1996; 106:
273 ± 279.
20 Ewert BH, Jennette JC, Falk RJ. The pathogenic role of anti-neutrophil
cytoplasmic autoantibodies. Am J Kidney Dis 1991; 18 188 ± 195.
21 Casselman BL, Kilgore KS, Miller BF, Warren JS. Antibodies to
neutrophil cytoplasmic antigens induce monocyte chemoattractant
protein-1 secretion from human monocytes. J Lab Clin Med 1995; 126:
495 ± 502.
22 Savage CO, Pottinger BE, Gaskin G, Pusey CD, Pearson JD.
Autoantibodies developing to myeloperoxidase and proteinase 3 in
systemic vasculitis stimulate neutrophil cytotoxicity towards cultured
endothelial cells. Am J Path 1992; 141: 335 ± 342.
23 Ewert BH, Jennette JC, Falk RJ. Anti-myeloperoxidase antibodies
stimulate neutrophils to damage human endothelial cells. Kidney Int
1992; 41: 375 ± 383.
24 Mayet WJ, Meyer zum Buschenfelde KH. Antibodies to proteinase 3
increase adhesion of neutrophils to human endothelial cells. Clin Exp
Immunol 1993; 94: 440 ± 446.
25 Mayet WJ, Schwarting A, Meyer zum Buschenfelde KH. Cytotoxic
effects of antibodies to proteinase 3 (C-ANCA) on human endothelial
cells. Clin Exp Immunol 1994; 97: 458 ± 465.
26 Van der Wiel BA et al. Interference of Wegener's granulomatosis
autoantibodies with neutrophil proteinase 3 activity. Clin Exp Immunol
1992; 90: 409 ± 414.
27 Mayet WJ et al. Human endothelial cells express proteinase 3, the
target antigen of anticytoplasmic antibodies in Wegener's Granulo-
matosis. Blood 1993; 82: 1221 ± 1229.
28 King WJ et al. Endothelial cells and renal epithelial cells do not
express the Wegener's autoantigen, proteinase 3. Clin Exp Immunol
1995; 102: 98 ± 105.
29 Heeringa P et al. Animal models of anti-neutrophil cytoplasmic
antibody associated vasculitis. Kidney Int (in press).
30 Mathieson PW, Thiru S, Oliveira DBG. Mercuric chloride-treated
Brown Norway rats develop widespread tissue injury including
necrotizing vasculitis. Lab Invest 1992; 67: 121 ± 129.
 Pathogenesis of vasculitis
CGM Kallenberg and P Heeringa
284
31 Hewicker M, Trautwein G. Sequential study of vasculitis in MRL
mice. Lab Anim 1987; 21: 335 ± 341.
32 Moyer CF, Strandberg DJ, Reinish CL. Systemic mononuclear cell
vasculitis in MRL=Mp-lpr=lpr mice: a histological and immunocyto-
chemical analysis. Am J Path 1987; 127: 229 ± 242.
33 Harper JM, Lockwood CM, Cooke A. Anti-neutrophil cytoplasm
antibody in MRL-lpr=lpr mice. Clin Exp Immunol 1993; 93(suppl 1): 22.
34 Kinjoh K, Kyogoku M, Good RA. Genetic selection for crescent
formation yields mouse strain with rapidly progressive glomerulo-
nephritis and small vessel vasculitis. Proc Natl Acad Sci 1993; 90:
3413 ± 3417.
35 Brouwer E et al. Anti-myeloperoxidase associated proliferative
glomerulonephritis; an animal model. J Exp Med 1993; 177: 905 ± 914.
36 Yang JJ, Jennette JC, Falk RJ. Immune complex glomerulonephritis is
induced in rats immunized with heterologous myeloperoxidase. Clin
Exp Immunol 1994; 97: 466 ± 473.
37 Heeringa P et al. Systemic injection of products of activated neutrophils
and H2O2 in myeloperoxidase-immunized rats leads to necrotizing
vasculitis in the lungs and gut. Am J Path 1997; 151: 131 ± 139.
38 Blank M et al. Immunization with anti-neutrophil cytoplasmic
antibody (ANCA) induces the production of mouse ANCA and
perivascular lymphocyte in®ltration. Clin Exp Immunol 1995; 102:
120 ± 130.
Downloaded from lup.sagepub.com at Bobst Library, New York University on June 4, 2015
39 Stegeman CA et al. Association of chronic nasal carriage of
Staphylococcus aureus and higher relapse rates in Wegener's
granulomatosis. Ann Intern Med 1994; 113: 12 ± 17.
40 Stegeman CA, Cohen Tervaert JW, Jong de PE, Kallenberg CGM.
Trimethoprim (Cotrimoxazole) for the prevention of relapses of
Wegener's granulomatosis. N Engl J Med 1996; 335: 16 ± 20.
41 Brouwer E et al. T-cell reactivity to proteinase 3 and myeloperoxidase
in patients with Wegener's granulomatosis. Clin Exp Immunol 1994;
98: 448 ± 453.
42 Leung DYM et al. Evidence for superantigen involvement in
cardiovascular injury due to Kawasaki syndrome. J Immunol 1995;
155: 5018 ± 5021.
43 Simpson IJ et al. Peripheral blood T lymphocytes in systemic
vasculitis: increased T cell receptor Vb2 gene usage in microscopic
polyarteritis. Clin Exp Immunol 1995; 101: 220 ± 226.
44 Popa ER et al. Skewed TCR Vb usage in Wegener's Granulomatosis
suggests stimulation by superantigens. J Am Soc Nephrol 1997; 8:
543A.
45 Posnett DN, Sinha R, Kabak S, Russo C. Clonal populations of T cells
in normal elderly humans: the T cell equivalents to `benign
monoclonal gammopathy'. J Exp Med 1994; 179: 609 ± 618.
46 Weyand CM, Goronzy JJ. Multisystem interactions in the pathogenesis
of vasculitis. Curr Op Rheumatol 1997; 9: 3 ± 11.