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Immunogenetic factors in inflammatory eye disease. influence of hlab27 and alpha1-antitrypsin phenotypes on disease expression

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143 1
IMMUNOGENETIC FACTORS IN
INFLAMMATORY EYE DISEASE
Influence of HLA-B27 and Alpha,-Antitrypsin Phenotypes
on Disease Expression
DENIS WAKEFIELD, SAMUEL N. BREIT, PEGGY CLARK, and RONALD PENNY
The relationship between the nature and severity
of inflammatory eye disease was analyzed with respect
to HLA antigens and alphal-antitrypsin phenotypes.
Using standard ophthalmologic criteria, we divided
patients with anterior uveitis into acute, chronic (>3month duration), bilateral, or recurrent disease. There
was a significantly increased incidence of alphal-antitrypsinaeficient phenotypes in anterior uveitis, especially in those patients with severe (chronic, bilateral, or
recurrent) disease. HLA-B27 acts as an independent
predisposing factor: it was present in 22% of patients
with their first attack of acute uveitis compared with
51% of patients with recurrent disease. Together, these
genetic factors are present in 63% of patients with
severe anterior uveitis and represent the most significant
predisposing and prognostic factors so far detected.
Despite extensive investigations, the pathogenesis of uveitis remains largely unknown. There is
From the Department of Immunology, St. Vincent’s Hospital and the Department of Medicine, University of New South
Wales; the Uveitis Research Clinic, Sydney Eye Hospital; and the
Institute of Clinical Pathology and Medical Research, Westmead
Hospital, New South Wales, Australia.
Denis Wakefield, MBBS: Research Fellow; Samuel N.
Breit, MBBS: Staff Specialist in Immunology; Peggy Clark, PhD:
The Institute of Clinical Pathology and Medicine Research, Westmead Hospital, New South Wales; Ronald Penny, MD: Associate
Professor of Medicine, St. Vincent’s Hospital and the Department
of Medicine, University of New South Wales, The Uveitis Research
Clinic, Sydney Eye Hospital.
Denis Wakefield and Samuel N. Breit are recipients of
National Health and Medical Research Council Postgraduate Fellowships.
Address reprint requests to Denis Wakefield, MBBS, Department of Immunology, St. Vincent’s Hospital, Sydney, 2010,
N.S.W., Australia.
Submitted for publication April 6, 1982; accepted in revised
form July 16, 1982.
Arthritis and Rheumatism, Val. 25, No. 12 (December 1982)
increasing evidence, however, that genetic factors
play a role in ocular inflammatory disease. This is
exemplified by the close association of HLA-B27 with
anterior uveitis (1) and, similarly, by a well-recognized
association of HLA-B5 in BehGet’s syndrome, complicated by uveitis or retinal vasculitis in Japanese and
Turkish populations (2). Recent evidence has also
implicated HLA-DRS in the chronic anterior uveitis of
juvenile polyarthritis (3). Children with this arthritic
syndrome, although not studied with regard to specific
subset, have been reported to have an increased
incidence of alpha,-antitrypsin deficiency (4).
The status of this separate genetic marker in
other forms of inflammatory eye disease remains controversial, despite its well-recognized association with
many other disorders. Severe alphal-antitrypsin deficiency, as is seen with the rare phenotypes PiSZ and
PiZZ, predisposes humans to emphysema and chronic
liver disease. Mildly deficient phenotypes such as
PiMZ and PiMS are quite common and are associated
with a number of diseases, including rheumatoid arthritis (5-7), systemic lupus erythematosus (7), asthma
(8), and fibrosing alveolitis (9). Since alpha,-antitrypsin is the major serine protease inhibitor in human
plasma, it is not unexpected that its absence might
predispose one to a variety of inflammatory diseases.
The study of the role of such genetic markers may
shed further light on the pathophysiology of these
disorders.
In the present study we analyzed the relationship between alphal-antitrypsin phenotype, HLA antigens, and the nature and severity of inflammatory eye
disease. The results demonstrated that alphaj-antitrypsin-deficient phenotypes substantially predispose
humans to chronic, bilateral, and recurrent anterior
WAKEFIELD ET AL
1432
uveitis (severe uveitis), while HLA-B27 appears to act
as an independent genetic predisposing factor in recurrent anterior uveitis. Together, these factors are present in 63% of cases of severe anterior uveitis. Our
findings reconcile the previous conflicting results on
the prevalence of alphal-antitrypsin deficiency in anterior uveitis and suggest an important role for this
protease inhibitor in this disease.
PATIENTS AND METHODS
Patient population. One hundred twenty-five subjects
were referred by ophthalmologists as part of our ongoing
study on inflammatory eye disease. After clinical assessment
by 2 independent ophthalmologists, patients were categorized as having anterior uveitis, posterior uveitis, or retinal
vasculitis. Anterior uveitis was defined as chronic if it
persisted for longer than 3 months despite topical steroid and
mydriatic therapy. Patients requiring systemic or retrobulbar
steroids were considered to have chronic anterior uveitis if
their disease flared and lasted more than 3 months after the
effective withdrawal of steroids. Recurrent anterior uveitis
was the diagnosis when the patient had 2 or more attacks of
uveitis separated by an asymptomatic and treatment-free
period of at least 1 month. Bilateral anterior uveitis referred
to the simultaneous involvement of both eyes. Patients with
chronic or bilateral anterior uveitis who suffered recurrent
disease were categorized as having recurrent anterior uveitis. Granulomatous uveitis occurred in 4 patients with
chronic disease, 2 of whom had sarcoidosis. Those patients
with recurrent, bilateral, or chronic anterior uveitis were
considered to have severe disease for the purpose of this
study.
Patients were independently classified without prior
knowledge of their alphal-antitrypsin phenotype. A population of 339 unrelated blood donors had previously been
studied to determine the normal distribution of alphalantitrypsin phenotypes. Patients and controls were white
and of comparable geographic and ethnic background. There
was no consanguinity in the patient population.
Alphal-antitrypsin phenotyping. This was carried out
on all subjects by the widely accepted technique of isoelectric focusing of serum samples on polyacrylamide gels at pH
3.5-5.0.
HLA typing. All patients were typed for the presence
of the B27 antigen. The first 50 consecutive patients were
also typed for HLA-A, B, and DR locus determinants.
Statistical analysis. This was carried out using a chisquare analysis or Fisher’s exact test when the sample size
in any subgroup was less than 5.
Etiologic investigations. All patients had a full blood
count, erythrocyte sedimentation rate, and biochemical
screen including liver function tests, calcium, urinalysis, and
angiotensin-converting enzyme. Tests were performed for
syphilis, Toxoplasma, viruses (influenza A and B, adenovirus, respiratory syncytial virus, herpes simplex), Q fever,
Mycoplasma pneumonia, and chlamydial. Delayed type hypersensitivity skin tests to tuberculosis, streptococcal, and
Candida antigens were also performed. Where indicated,
chest and joint radiology was performed.
RESULTS
Table 1 summarizes clinical associations and
Table 2, the incidence of different alphaI-antitrypsin
phenotypes in the patient population. There were no
differences between groups with respect to the dosage,
frequency, or duration of topical steroid therapy except for patients with chronic anterior uveitis, 3 of
whom required retrobulbar steroids. Systemic steroids
were required to control uveitis in chronic and recurrent anterior uveitis (3 and 5 patients, respectively);
posterior uveitis (8 patients); and retinal vasculitis (7
patients). No patient in the acute anterior uveitis group
required systemic or retrobulbar steroids. Alphalantitrypsin deficiency was associated with the idiopathic group of uveitis patients (Table 1); no other
particular etiologic group had a statistically significant
prevalence of alphal-antitrypsin-deficient phenotypes.
HLA-B27 was the only HLA antigen significantly associated with inflammatory eye disease.
However, HLA typing of those patients with alpha,antitrypsin phenotype MS revealed that 4 of 6 had the
HLA-DR5 antigen (P < 0.01). To investigate further
Table 1. Clinical associations of inflammatory eye disease
~~
Anterior uveitis
Etiology
Acute
Bilateral
Recurrent
Chronic
Posterior
uveitis
Retinal
vasculitis
Idiopathic
Ankylosing spondylitis
Reiter’s syndrome
Ulcerative colitis
Sarcoidosis
Behcet’s syndrome
Juvenile chronic arthritis
Pars planitis
Toxoplasrnosis
Tuberculosis
Herpes simplex
26
6
3
19
10
10
5
18
4
1
3
I
2
1
1
1
I
4
5
1
1
2
IMMUNOGENETICS OF EYE DISEASE
1433
Table 2. Alpha,-antitrypsin phenotypes in inflammatory eye
disease
in patients with anterior uveitis; this was most prevalent in those patients with chronic (40%), bilateral
(60%), or recurrent (20%) disease (Table 3). By contrast, none of the 36 patients with a solitary episode of
anterior uveitis after a 6-month followup period was
found to be alphal-antitrypsin deficient. Thus, alpha,antitrypsin deficiency appears to predispose to a more
severe and recurrent inflammatory response in the iris;
all patients who were alpha,-antitrypsin deficient had a
more severe or complicated disease.
Previous reports on the association of deficient
alpha,-antitrypsin phenotypes with uveitis have been
controversial. Brewerton et a1 (10) found that alphalantitrypsin-deficient phenotype MZ was present in 20
(25%) of their 80 patients with acute anterior uveitis
compared with a prevalence of 3% in the control
population. This association was not substantiated by
Brown et a1 (1 I), who found no increased association
of the MZ phenotype in their 133 patients with acute
anterior uveitis. The present study may serve to
explain these previous discrepancies. Overall, there is
only a slightly increased but statistically significant
incidence of deficient phenotypes (MS) in anterior
uveitis. However, when we carefully categorized patients as to the nature and severity of their disease, it
was evident that the more severe subtypes of anterior
uveitis displayed a marked increase in the incidence of
alphal-antitrypsin-deficient phenotypes (Table 2).
Such differences in uveitis severity in the study populations may well lead to considerable differences in the
overall incidence of alpha,-antitrypsin deficiency.
In agreement with previous studies (l), the
HLA-B27 antigen was present in 31% of our patients
with anterior uveitis; 71% of these had recurrent
disease. There was a 20% incidence of alphal-antitrypsin phenotypes in recurrent anterior uveitis. The
HLA-B27 and alphal-antitrypsin-deficient phenotypes are both associated with recurrent disease and
appear to act as independent variables. They may
serve, therefore, not only as genetic markers for the
~~
~-
~
% phenotype
Disease (no. of patients)
Anterior uveitis
Acute (36)
Chronic (10)
Bilateral (5)
Recurrent (39)
Posterior uveitis (16)
Retinal vasculitis (19)
Controls (339)
MM
MS
MZ
MS and/or MZ
loo*
60*t
0
40*t
0
0
20
5
12
5
4
O*
40*t
40t
80t
40*t
71
5
84
11
7
89
15*t
60*t
20*t
17
16
I1
* P < 0.001-0.05 compared with controls.
t P < 0.05 compared with acute anterior uveitis.
the significance of this finding, I0 healthy controls
known to have the HLA-DRS antigen were phenotyped; none were found to have the MS phenotype.
MM is the most commonly encountered phenotype in the community; it occurs in 90% of the
population. There was a decrease in this phenotype
corresponding to an increase in the MS phenotype.
Fifty-one percent of patients (20 of 39) with recurrent
anterior uveitis were HLA-B27 positive compared
with 22% of patients (8 of 36) presenting with their first
attack of acute anterior uveitis. There was no difference in the distribution of alphal-antitrypsin-deficient
phenotypes between the HLA-B27-positive and
HLA-B27-negative patients. The relative risk for recurrent disease in those patients who were HLA-B27
positive was increased 3.7 times, whereas the relative
risk for those patients with uveitis who were HLA-B27
positive and/or had a deficient phenotype was increased
7.9 times. A summary of the significant results and
relative risk data is given in Table 3. Patients presenting
with their first attack of anterior uveitis had a 40%
chance of developing further attacks.
DISCUSSION
Our results indicate a significantly increased
incidence of alphal-antitrypsin deficiency (MS or MZ)
Table 3. Distribution of genetic risk factor in anterior uveitis (5%)
~~
No.
Acute uveitis
Severe uveitis
Recurrent
Chronic
Bilateral
36
54
39
10
5
~
Alpha,-antitrysin
deficiency*
0
28%
20*
40 *
hO*
HLA-B27+
t
22
37(2. I )
51(3.7)
0
0
* Relative risk high but incalculable.
t Number in parentheses indicates relative risk compared with acute uveitis.
Alpha,-antitrypsin
deficiency and/or
HLA-B27+ t
WAKEFIELD ET AL
1434
disease but also as important prognostic indicators in
early disease, knowledge of which may eventually
alter our therapeutic approach to this condition.
The high frequency of HLA-DRS in those patients with severe anterior uveitis and the MS phenotype may be important in view of the recently reported
increased incidence of this antigen in those patients
with the chronic anterior uveitis of juvenile chronic
arthritis (3). Such a small sample may be unrepresentative, however, and needs confirmation. The genetic
locus for alphal-antitrypsin is on chromosome 14 (12)
and thus separate from HLA antigen locus on chromosome 6.
The mechanism for the disease association of
anterior uveitis and alpha,-antitrypsin deficiency is not
fully understood. However, the role played by protease inhibitors and their regulation of the inflammatory
and immunologic responses is probably of fundamental importance (13,14).
Alpha,-antitrypsin is an inhibitor of serum proteases with activity against a wide variety of enzymes,
including leukocyte neutral proteases, elastases, collagenase, trypsin, and thrombin (15). It has a low
molecular weight and the highest molar concentration
of any protease inhibitor. This and the fact that it is an
acute-phase reactant allow it to achieve a ubiquitous
distribution in both intra- and extravascular compartments. Deficient phenotypes of alphal-antitrypsin
have a reduced capacity to respond as acute-phase
reactants (16) and thus may not be able to adequately
regulate activated enzymes in the inflammatory and
immunologic responses. In such deficient patients,
abnormalities in immunoregulation may predispose
them to uveitis and may allow more prolonged and
severe uveitis to occur, as observed in this study.
Our results indicate the importance of the
HLA-B27 antigen and alphal-antitrypsin phenotype as
immunogenetic markers that predispose the patient to
inflammatory eye disease and influence the nature and
severity of the disease. Knowledge of such genetic
factors may not only aid our understanding of the
mechanism involved in this illness but also serve as
significant prognostic factors in following the course of
the disease.
ACKNOWLEDGMENTS
The authors wish to acknowledge the secretarial
assistance of Jill Kramer and Kim McKinnon and the
technical help of Helen Blake, Claire Molenaar, and Beverley Russell. Tissue was typed by the laboratories of the Red
Cross Transfusion Service, Sydney, New South Wales.
REFERENCES
1. Brewerton DA, Caffrey M, Nicholls A, Walters D,
James DCO: Acute anterior uveitis and HLA B27.
Lancet 1:994, 1973
2. Lehner T, Barnes CG, editors: Behcet’s Syndrome
Clinical and Immunological Features. New York, Academic Press, 1979
3. Glass D, Litvin D, Wallace K , Chylack L, Garovdy M,
Carpenter CB: Early onset pauciarticular juvenile rheumatoid arthritis associated with human leukocyte antigen DRW5, iritis, and antinuclear antibody. J Clin Invest
66:426-429, 1980
4. Arnaud P, Galbraith RM, Faulk WP, Ansell BM: Increased frequency of the MZ phenotype of alpha 1
protease inhibitor in juvenile chronic polyarthritis. J Clin
Invest 60:1442-1444, 1977
5. Cox DW, Huber 0: Rheumatoid arthritis and alpha I
antitrypsin. Lancet 1:1216-1217, 1976
6. Buisseret PD, Pembrey ME, Lessof MH: Alpha 1 antitrypsin phenotypes in rheumatoid arthritis and ankylosing spondylitis. Lancet 2: 1358-1359, 1977
7. Breit SN, Clark P, Penny R: Alpha 1 protease inhibitor
(alpha 1 antitrypsin) phenotypes in rheumatic diseases
(abstract). Aust NZ J Med 10:271, 1980
8. Arnaud P, Chapuis-Cellier C, Souillet G, Carron R,
Wilson GB, Creyssel R, Fudenburg HH: High frequency
of deficient Pi phenotypes of alpha 1 antitrypsin in
nonatopic infantile asthma. Trans Assoc Am Physicians
89:205-2 14, 1976
9. Geddes DM, Webley M, Brewerton DA, Turton EW,
Turner-Warwick M, Murphy AH, Milford Ward A:
Alpha 1 antitrypsin phenotypes in fibrosing alveolitis
and rheumatoid arthritis. Lancet 2: 1049-1050, 1977
10. Brewerton DA, Webley M, Murphy AH, Milford Ward
A: The alpha 1 antitrypsin phenotype MZ in acute
anterior uveitis. Lancet 1:1103, 1978
11. Brown WT, Mamelok AE, Bearn AG: Anterior uveitis
and alpha 1 antitrypsin. Lancet 1:646, 1979
12. Cox DW, Markovic VD, Teshina IE: Genes for immunoglobulin heavy chains and for alpha 1 antitrypsin are
localised to specific regions of chromosome 14q. Nature
297:428-430, 1982
13. Breit SN, Penny R: The role of a 1 protease inhibitor ( a
1 antitrypsin) in the regulation of immunologic and inflammatory reactions. Aust NZ J Med 10:449-453, 1980
14. Breit SN, Robinson JP, Luckhurst E, Clark P, Penny R:
Immunoregulation by alpha 1 antitrypsin. J Clin Lab
Immunol 7: 127-132, 1982
15. Travis J, Matheson N , Johnson D: The interaction of
alpha 1 protease inhibitor with serine proteinases,
Chemistry and Biology of Thrombin. Edited by RL
Lundblad. Ann Arbor, Ann Arbor Science, 1977, pp
43 1-440
16. Kueppers F: Genetically determined differences in the
response of alpha 1 antitrypsin levels in human serum to
typhoid vaccine. Hum Genet 6:207-214, 1968
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expressions, antitrypsin, factors, immunogenetics, alpha, phenotypic, inflammatory, disease, hlab27, influence, eye
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