Vascular Damage in Humans Develops on Various Grounds

8/18/2019 Vascular Damage in Humans Develops on Various Grounds

1/11

Vascular damage in humans develops on various grounds. It may be inflammatory or

noninflammatory. The damages may be induced by environmental factors (toxic agents,

medications, microorganisms), through cancer as a paraneoplastic syndrome, or may be directly

associated with an active immune process. Systemic lupus erythematosus (S!) is a connective

tissue autoimmune disease, where vasculopathy is one of the typical symptoms. It is reported in

"#$%#& of patients. It occurs more often in women ('#&) than in men and may precede the

development of a fullblown S!.

The differentiation of the type of vascular complications is very difficult, sometimes impossible,

and reuires an indepth immune, histopathologic and imaging diagnostic approaches, and

extensive clinical experience. It may play a *ey role in the choice of treatment strategy and

prediction of the patient prognosis. Therefore, the awareness of the etiology, pathophysiology,

the clinical and histopathogical setting, and S! associated vascular complications is of great

clinical significance.

Vascular lesions in S! are commonly *nown as the lupus vasculopathy+ a typical lupus

vasculitis with inflammatory and vascular wall necrosis and a thrombus in the lumen of affected

artery occurs less often. ppel et al. provided an S! vasculopathy classification including- non

complicated vascular deposits of immune complexes, noninflammatory necrotic vasculopathy,thrombotic microangiopathy and true lupus vasculitis. f all lupus vasculitis, cases more than

/#& is leucocytoclastic inflammation, 0#& is vasculitis with cryoglobulinemia, and systemic

vasculitis resembling polyarteritis nodosa constitutes about /& of S! vasculitides patients.

ther clinical syndromes of vasculopathy in patients from the discussed group include

thrombocytopenia with thrombotic purpura, venous thrombosis, antiphospholipid syndrome and

urticaria vasculitis, reported in 1& of S! patients.

The systemic lupus erythematosus associated vasculitis may present different clinical courses.

The broad spectrum of symptoms includes mild forms affecting only cutaneous vessels, and also

severe, catastrophic forms, with organ complications development, and vasculitis within the

internal organs. upus vasculopathy is usually seen in cutaneous vessels, in renal glomeruli,

coronary and brain vessels, the brain, lung alveoli and less often in the gastrointestinal tract. It


2/11

has to be stressed that cutaneous lupus vasculopathy in S! occurs most often, and is reported in

2%& of patients with lupus vasculitis. 3ild forms are characteri4ed by purpura, urticaria lesions

or bullous lesions of extremities, and livedo reticularis on the trun* . 5ith a more severe course,

digit ulcerations and necrosis of the nail bed occur, and cryoglobulinemic vasculitis coexists with

cutaneous lesion. 6linically, %#& of cutaneous lesions have the form of discoid erythematosus

lesions usually located on fingertips, 0#& have the form of the erythema of the hand dorsum, and

7#& of them are nodular lesions . 8ive percent of patients experience subcutaneous vasculitis.

It has been demonstrated that internal organ vessels are affected in "'& of S! vasculitis

patients . 9enal vasculitis ta*es the shape of focal segmental glomerulitis with development of

fibrinoid necrosis . ung vasculitis ta*es the form of necrotic alveolar capillaritis predisposing to

pulmonary hemorrhage . :rain vasculitis occurs only in about "#& of S! patients, and

associated clinical symptoms are very variable+ from a mild cognitive dysfunction to severe

psychosis and convulsions, local ischemia and stro*es. The peripheral nervous system may also

be affected by lupus vasculopathy leading to multifocal inflammatory mononeuropathies .

3esothelium vasculitis may also occur and lead to gastrointestinal hemorrhage or perforation .

Pathophysiology of vasculopathy and vasculitis in SLE

Vasculopathy in S! and in other autoimmune systemic diseases and infections is secondary

vasculitis, however the pathogenesis of these diseases has not been fully elucidated .

s mentioned above, S! vasculopathy may be of inflammatory or thrombotic origin . :oth

mechanisms involve the immune system, and the activation and conseuent endothelial lesions

play a very important role in the disease pathogenesis. It seems that endothelial cells activation

with pronounced expression and activation of adhesive molecules are the *ey factors in the

pathogenesis of this disease. ctivated endothelial cells are able to bind various proteins and

cells to the vessel wall . This process is at first limited only to postcapillary venules, which are

often affected in the small vessel disease . ;owever, vasculitis locali4ation in arterial branching

is most probably the result of compression forces . The damage locali4ation may also depend

upon the hydrostatic pressure values and local blood circulation disorders .


3/11

The common hypothesis for S! vasculopathy concerns the endothelial deposition of circulating

immune complexes. The conseuent, secondary inflammatory response activates the complement

cascade, most probably with 61b2 complex formation, destroying vascular basal membranes .

;owever, there are also other mechanisms causing the immune response antigen to be primarily

located in the vessel wall. 8or example, the nucleohistone adhesion to the vessel basement

membrane in lupus nephritis results in secondary antibody binding, and the locally formed

complex may be the cause of immune vacsulitis. 3oreover, the immune complexes clearance

decreases, and the tissue factor expression is upregulated which also may contribute to lupus

S! vasculopathy. 3ost probably, also the 6" complement component and its receptor in the

endothelial cellular membrane may ta*e part in endothelial activation


4/11

and >?histon complexes, @ and / ribosome protein, elongation factor " a, adenyl cyclase

associated protein, profilin II, plasminogen activator inhibitor, fibronectin and A7glicoprotein I.

It is worth stressing that !6 are not specific to endothelial cells, as antigen determinants for

them are also present on fibroblasts, leu*ocytes and blood monocytes . The discussed antigens

induce a proinflammatory and proadhesive endothelial cell phenotype through the ?8B:

activation pathway. The !6 endothelial cell influence is associated with the concentration of

these antibodies and causes the increases of functional monocyte adhesion, and the adhesion

molecules expression such as !selectin, intercellular adhesion molecule " (I63"), vascular

cell adhesion molecule " (V63"), as well as enhanced secretion of chemoattractant proteins

and cyto*ines such as monocyte chemoattractant protein" (36@") and interleu*in" (I"),

interleu*in/ (I/) and interleu*in' (I').

In S! patients, !6 may bind the compliment and most probably this mechanism also is

involved in vasculitis, yet this is still under discussion. >el @apa et al. demonstrated that plasma

from systemic vasculitis patients displayed !6 antibodyassociated cytotoxicity, which occurs

uniuely in the presence of lymphocytes. The monoclonal !6 cause increased I/ secretion,

which may accelerate the lymphocyte infiltration rate, causing vascular damage.

The antiendothelial cell antibodies of Ig= class probably activate leu*ocytes which infiltrate the

blood vessel wall. The in vitro experiments demonstrated enhanced leu*ocyte adhesion to human

umbilical vein endothelial cell, depends on higher expression adhesion molecules . This creates

conditions for maintaining close cell contact with the vessel wall and for proinflammatory

endothelial cell activation, manifested by adhesion molecule expression and increased cyto*ine

secretion .

The !6 may induce endothelial cell apoptosis independently of 8c receptor C7",7/D. The

presumable !6 antigen determinant in the apoptosis process is heat shoc* protein(;S@) /#

C7/D. crossreaction between !6 and ;sp/# has been demonstrated in S! vasculitis

patients C7ED.


5/11

It is believed that !6 ta*e part in thrombus formation in S! patients C7'D. They may react

with various components of endothelial cells and extracellular matrix, including proteoglycan

molecules, bound with negatively charged glycosamino glycans (==), i.e. heparan sulfate and

hyaluronate C7'D. >ires*eneli et al. C7'D demonstrated that heparin inhibits the effect ascribed to

!6 in a dosedependent manner. The endothelial cell activation that is !6 dependent may

induce prothrombotic lesions as a result of increased release of plasminogen activitator inhibitor

" (@I"), platelet activating factor C71D and thrombomodulin, together with enhanced von

5illebrand factor synthesis C7#,7"D. It has been suggested that soluble thrombomodulin is a

mar*er of endothelial damage in the microcirculation .

It is worth mentioning that the !6 probably ta*e part in urticarial vasculitis with the 6"

deficiency and the Ig= anti6" antibody presence . It is suggested that these antibodies may

specifically induce clinical symptoms including angioedema, Foint pain, eye inflammation,

glomerulonephritis and chronic obstructive pulmonary disease .

In summary, although a potential role of the !6 in the vasculitis pathogenesis has not been

fully determined yet, several lines of evidence have demonstrated that !6 is a factor that

causes endothelial damage in S! C","1,7#,77,7%,7'D.

Antiphospholipid antibodies

It has been suggested that endothelial damage of whatever origin exposes endothelial cell

phospholipids, which enables the adhesion of antibodies directed against phospholipids (a@) .

These antibodies cause further vascular endothelial damage, an increased arterial and venous

thrombosis ris* and proliferative heart valve lesions . It has been postulated that a@ antibodies

perturb endothelial function, and promote thrombus formation during infection or pregnancy .

The antigen specificity of a@ antibodies includes the negatively charged cell membrane

phospholipids, i.e. cardiolipin (6), diphosphate glycerol, phosphatidyl ethanol amine,

phosphatidyl ethanol serine . ysophosphatidylcholine (@6) may also induce an immune

reaction, leading to vascular inflammatory lesions, and other S! symptoms . In S! patients, a

clinical syndrome including the presence of a@ and vascular thrombi is now *nown as the


6/11

secondary antiphospholipid syndrome . It is worth mentioning that the A7glicoprotein I, and

other plasma proteins may change the phospholipid antigenecity through neoantigen formation .

The pathogenetic action mechanisms of a@ antibodies are variable. 5hen binding with

membrane phospholipids a@ antibodies may inhibit reactions cataly4ed by them in the

coagulation cascade, for example through inhibition of 6 and S protein activation . These

antibodies may also activate endothelial cells thrombin formation . The binding of a@

antibodies with platelet membrane phospholipids binding protein predisposes to platelet

activation and adhesion, with conseuent thrombus formation . These antibodies probably also

participate in the complement system activation . s a result, the a@ antibodies demonstrate

proadhesive, proinflammatory and prothrombotic effects on endothelial cells . The activity of

a@ antibodies may also be lin*ed to the development of early atherosclerosis in S! patients .

Antineutrophil cytoplasmic autoantibodies

The antineutrophil cytoplasmic autoantibodies (?6) are directed against cytoplasmic

antigens contained in a4urophilic granules of neutrophils and monocyte lysosomes. These

antibodies belong to a heterogeneous family and are reported in all immunoglobin classes.

ccording to indirect fluorescent labeling images, there are cytoplasmic (c?6) and

perinuclear ?6 (p?6), and atypical c?6 and ?6, forms. The c?6 antibody

activity is directed against the proteinase 0 (@90), while p?6 antibodies activity is directed

against myeloperoxidase (3@). It should, however, be stressed that they react also with other

proteins.

Initially, the ?6 presence was associated only with primary systemic vasculitits. relation of

c?6 (@90?6) with 5egeners granulomatosis, and that of p?6 (3@ ?6) with

microscopic polyangiitis, and crescentic glomerulonephritis, has been demonstrated. It is *nown

however that ?6 antibodies occur also in secondary vasculitides associated with systemic

connective tissue diseases, including S!. In "1$7# & of S! patients, ?6 antibodies,

usually p?6, have been reported .


7/11

Vasculitis in S! patients is a well documented phenomenon+ however, the ?6 antibodies

role in the inflammation pathogenesis is still under discussion . The relation between the p?6

titer and S! activity has not been confirmed yet, in particular that the relation between the

mentioned antibodies presence and S! specific organ complications has not been

demonstrated . Therefore, conclusions from available studies remain ambiguous .

The antineutrophil cytoplasmic autoantibodies associated vasculitis is characteri4ed by the

occurrence of focal necrotic foci of capillaries, venules and sometimes arterioles . It is suggested

that necrosis development may be the result of microcirculation seuestration of activated

neutrophiles and monocytes. Various cyto*ines, chemo*ines, bacterial lipopolysaccharides and

intestinal toxins activated cells are to increase the a4urophilic granules membrane expression,

which contain the ?6 specific antigens, @90 or 3@ . t this stage ?6 by binding and

forming immune complexes with @90 or 3@ would be to activate neutrophil adhesion to

endothelial cells, with conseuent extravascular permeation, vessel damage and apoptosis

development. direct involvement of integrin and cyto*ine receptors, and a protective effect of

A7integrin antibodies in endothelial damage have been demonstrated . It has also been shown

that the Ig=, @90?6 antibodies stimulate neutrophil degranulation and lysosome en4yme

release, highly reactive forms of oxygen and nitric oxide. These forms and lysosome en4ymes

most probably cause damage to the vascular basement membrane . The released @90, ta*ing part

in proteogli*an and elastin degradation, would be to cause damage of endothelial cells and

induce apoptosis in them . The activating effect of @90 and 3@ on T helper 6>% lymphocytes

proliferation, has also been postulated . 3ost probably ?6 also ta*e part in inflammation,

inhibiting @90 binding with the G"antitrypsin inhibitor and, as a result, decreasing the antigen

and immune complexes decomposition . The ?6 role in systemic vasculitis in S! patients,

so far remains unclear.

Anti-double-stranded DNA antibodies

ntidoublestranded >? antibodies (antids>?) antibodies may ta*e part in vascular

damage in S!. They possess an antiendothelial activity, which is directed against certain

antigens on endothelial surface . Their direct cytotoxic effect on endothelial cells has not,

however, been demonstrated . The synthesis of I" and I/ induced by the antids>?


8/11

antibodies has only been demonstrated, which can indirectly indicate endothelial cell activation.

The anti >?histone complexes antibodies have a similar effect . dditionally, circulating

>? fragments contribute to S! vasculitis pathogenesis . The endothelial cells I63"

expression stimulation, and the m9? I/, I', T?8G, I8?H synthesis increase, with

participation of >? fragments, has been shown .

Cellular adhesion molecules

6ellular adhesion molecules enable the leu*ocyte adhesion and rolling along the endothelial cells

surface, and control leu*ocyte permeation to inflammation affected tissues. !nhancement of

granulocyte cell surface, and endothelial, adhesion molecules expression, determines the

adhesion of these molecules to the vascular wall and their secondary permeation to extravascular

space. The adhesion molecules are also a molecular signal for the immune memory lymphocytes

towards a certain antigen and enable a constant lymphocyte flow through tissues, where a certain

antigen has been discovered for the first time.

6ellular adhesion molecules are classified to 0 groups, i.e. selectins, integrins and

immunoglobulin superfamily (I=S8).

!Selectin expression is limited to activated endothelial cells. !Selectin influences the initial

adhesion of nonactivated leu*ocytes (neutrophils, monocytes and immune memory T

lymphocytes) to activated endothelial cells and enables leu*ocyte rolling and possibly plays the

role of an intracellular transmitter. !selectin expression is stimulated by I" and T?8G. !

selectin is the specific inflammatory mar*er, of endothelial cell activation.

The leu*ocyte surface integrins are the ymphocyte functionassociated antigen" (8"), and

very late antigen % (V%). The integrins bind with the I=S8 group receptor, which contains

adhesion molecules, I63" and V63". The expression of both adhesion molecules on the

endothelium surface reuires inflammatory cyto*ine induction, T?8G, I" and I8?H. The

adhesion molecule V63" reacts with cells with the V% chain expression in monocytes,

lymphocytes, macrophages, glomerular parietal epithelial cells, basophils and eosinophils.


9/11

In S! associated necroti4ing vasculitis there is increased V% expression, which binds with

the fibronectin 6S" domain. This process enables T lymphocyteactivated endothelial cell

adhesion.

\

he role of cellular adhesion molecules in SLE vasculitis

In S! patients there are alterations in cellular adhesion molecule expression. @redominant

adhesion molecules locally participating in S! inflammation formation are most probably !

selectin, I63" and V63" with their ligands, i.e. Sialyl ewis (se), 8" and V

% . It has been demonstrated that 8" expression on peripheral blood lymphocytes is increased

in the S! patient group . Increased levels of 8" and V% in vasculitis patients have also

been reported . The antids>? and class Ig= 6! antibodies have been reported to increase

expression of cellular adhesion molecules . ntibodies and immune complexes created with their

participation induce the cyto*ine synthesis and increase the endothelial cells adhesion


10/11

molecules expression, with a resulting granulocyte aggregation secondary effect . The induction

of I63" and V63" expression in ;JV!6 with the use of purified Ig= from S! patients,

has been demonstrated . closer endothelial cell lymphocyte adhesion in active S! patients,

has not, however, been demonstrated, and results of studies dealing with this issue were

contradictory . 3oreover, T lymphocytes of patients with active S! and accompanying

lymphopenia were characteri4ed by the I" stimulated decreased adhesion potency to ;JV!6 .

It is postulated that cells of potent adherence may be eliminated from the blood stream, which

could explain the lymphocyte count decrease in active S! .

Soluble forms of adhesion molecules

Increased levels of soluble forms of adhesion molecules and I/ are reported in plasma of S!

patients, indirectly indicating endothelial cells activation . These molecules are en4ymatically

released from the cyto*ineactivated cell surface. Several studies demonstrated a correlation

between their levels and the disease activity. In the S! patients, plasma sV63", soluble !

selectin and sI63" levels are increased . It has been shown that sV63" levels correlated

with S! activity . The sV63" serum levels were increased in the active forms of lupus

nephritis such as in neuropsychiatric S! and deep vein thrombosis associated with

antiphospholipid syndrome in S! patients . The sV63 " titer correlated with severe

thrombotic complications and thrombotic microangiopathy with renal failure . It has also been

demonstrated that the levels of all soluble adhesion molecules such as sV63", sI63" and

s!selectin, correlated with the a@ titer . relation between sV63" and soluble

trombomodulin has been demonstrated . The s!selectin and sI63" increase in S! vasculitis,

however, is believed to be a multiorgan damage mar*er. There are suggestions that soluble

adhesion molecules may play a protective role in S!. It has been postulated that the soluble

!selectin may protect against lupus nephritis development . Several authors suggest that it could

exert physiological effects by influencing interactions between endothelial cells and circulating

leu*ocytes+ other studies, however, demonstrated that s!selectin is rather a inactive

decomposition product . Similar findings refer to the role of s@selectin .

Drug-induced vasculitis in SLE


11/11

Some drugs may play a role in the induction of inflammatory vascular lesions in S!. The drug

molecule may act as a hapten, which as a result of autoantigen binding alters the antigen

properties. Several S! inducing drugs are listed below- penicillins, allopurinol, thia4ides,

pyra4olones, retinoids, strepto*inase, cyto*ines, monoclonal antibodies, chinolons, hydantoin,

carbama4epine and other anticonvulsants .

!nfection-induced SLE vasculitis

Vasculitis may be a result of direct attac* of microorganisms on the blood vessel wall or may be

caused by infected thrombotic mass. ;epatitis 6 virus may ta*e part in vasculitis development,

with the cryoglobulin presence. This factor participation should be considered in S! patients

with large blood vessel inflammation of the lower extremities. There is an unexplained

relationship between blood cryoglobulins and hepatitis 6. The following mechanisms leading to

viral and bacterial vasculitis in S! have been suggested- ") the viruses directly attac* the

vascular wall inducing an inflammatory process 7) some of them, as cytomegalovirus, may

permeate and activate endothelial cells leading to vasculitis 0) bacterial Staphylococcus antigens,

as for example neutral phosphatase, may bind with basement membranes and adhere specifically

to Ig=, which in turn induces an immune response and an inflammatory process.

Vascular Damage in Humans Develops on Various Grounds

Documents

Transcript of Vascular Damage in Humans Develops on Various Grounds