Immunopathology of the Noninfectious Posterior and Intermediate Uveitides

doi:10.1016/S0039-6257(01)00275-2

Survey of Ophthalmology

Volume 46, Issue 3, November–December 2001, Pages 209-233

https://doi.org/10.1016/S0039-6257(01)00275-2 Get rights and content

Abstract

The posterior and intermediate uveitides share an underlying immune etiology; however, they can be clincally and immunopathologically distinguished. Although the initiating stimuli for posterior and intermediate uveities are not known, it is believed that an exogenous agent (such as a bacterium or a virus) or an endogenous molecule may induce disease. In either case, T-helper lymphocytes in conjunction with human leukocyte antigens are likely to be involved. This review examines the epidemiology, histology, immunopathology, and theories of pathogenesis of several posterior and intermediate uveitides, including sympathetic ophthalmia, Vogt–Koyanagi–Harada syndrome, Behçet's disease, sarcoidosis, intermediate uveitis, white dot syndromes, and birdshot retinochoroidopathy.

Section snippets

Mechanisms of Immune Disease

Overall, it is believed that an initiating stimulus triggers immune disease, and that once initiated, the cellular and molecular interactions between subsets of T lymphocytes determine the clinical course. Moreover, it is also likely that both environmental and genetic factors modify disease susceptibility and expression. The association, at least in some patients, between the inheritied immunoregulatory molecules, the human lymphocyte antigens (HLA) and uveitis, and the clinical use of

Sympathetic ophthalmia

Sympathetic ophthalmia (SO) is a bilateral inflammatory disease that occurs following penetrating trauma to one eye.277, 393 Incidence rates of 0.19% and 0.07% have been reported for accidental or surgical trauma, respectively, and occasional reports suggest that sympathetic ophthalmia can follow nonpenetrating trauma to uveal tissue by cryotherapy, laser cycloablation, or radioactive plaque therapy.84, 191, 192, 215, 226, 391 The onset may occur between 5 days and 66 years following trauma,

Summary

Often grouped together under the collective terms posterior uveitis and intermediate uveitis, it is clear that the uveitides discussed in this review all share an underlying immune etiology, yet can be clinically and immunopathologicially distinguished. Recognized differences include the inciting stimulus, the nature of the suspected antigen, the immune cell repertoire most notably the predominant T lymphocyte subset, the types of cytokines produced by these cells, and the subsequent cascade of

Conclusion and Future Directions

In summary, each of the noninfectious posterior and intermediate uveitides may result from an immunogenetic predisposition to disease and development of an inappropriately directed immune response. Traumatic presentation of a self-antigen, or exposure to a self-similar antigen may trigger inflammation. Activation of T lymphocytes and the cytokines they produce then determine the nature of the ensuing response; once initiated, ongoing antigen presentation and epitope spreading increase its

Method of Literature Search

Literature selection for this article was based initially on a MEDLINE search using the following keywords: human, uveitis, posterior, SO, VKH, Behçet's, sarcoid, intermediate uveitis, pars planitis, white dot, birdshot, pathology, immune, immunology, lymphocyte, cytokine, and antibodies. References were also obtained from major textbooks including, among others, Nussenblatt, Uveitis: Fundamentals and Clinical Practice, Mosby 1996, and Albert and Jakobiec, Principles and Practice of

Outline

I. Mechanisms of immune disease

II. The posterior and intermediate uveitides

A. Sympathetic ophthalmia

1. Clinical observations

2. Histology

3. Immunopathology

4. Nonocular investigations

5. Theories of pathogenesis

B. Vogt–Koyanagi–Harada Syndrome

1. Immunogenetics

2. Clinical observations

3. Histology

4. Immunopathology

5. Nonocular investigations

6. Theories of pathogenesis

C. Behçet's disease

1. Immunogenetics

2. Clinical observations

3. Histology

4. Immunopathology

5. Nonocular investigations

6. Theories of

References (441)

C Alaez et al.
Strong association of HLA class II sequences in Mexicans with Vogt– Koyanagi–Haradas disease
Hum Immunol
(1999)
K Ando et al.
Epidemiological features and visual prognosis of Behçet's disease
Jpn J Ophthalmol
(1999)
A.O Aydintug et al.
Antibodies to endothelial cells in patients with Behçet's disease
Clin Immunol Immunopathol
(1993)
P Azar et al.
Acute posterior multifocal placoid pigment epitheliopathy associated with an adenovirus type 5 infection
Am J Ophthalmol
(1975)
S.P Azen et al.
Histocompatibility antigens in sympathetic ophthalmia
Am J Ophthalmol
(1984)
E Ben-Chetrit et al.
Colchicine1998 update
Semin Arthritis Rheum
(1998)
D Benezra et al.
Blood serum interleukin-1 receptor antagonist in pars planitis and ocular Behçet disease
Am J Ophthalmol
(1997)
D BenEzra et al.
Serum levels of interleukin-2 receptor in ocular Behçet's disease
Am J Ophthalmol
(1993)
R.E Braley et al.
The prevalence of HLA-B7 in presumed ocular histoplasmosis
Am J Ophthalmol
(1978)
D Callanan et al.
Multifocal choroiditis and choroidal neovascularization associated with the multiple evanescent white dot and acute idiopathic blind spot enlargement syndrome
Ophthalmology
(1992)

C.C Chan

Relationship between sympathetic ophthalmia, phacoanaphylatic endophthalmitis, and Vogt–Koyanagi–Harada disease

Ophthalmology

(1988)

C.C Chan et al.

Sympathetic ophthalmia. Immunopathological findings

Ophthalmology

(1986)

C.C Chan et al.

Immunopathologic study of Vogt–Koyanagi–Harada syndrome

Am J Ophthalmol

(1988)

C.C Chan et al.

Anti-retinal auto-antibodies in Vogt–Koyanagi–Harada syndrome, Behçet's disease, and sympathetic ophthalmia

Ophthalmology

(1985)

I.J Check et al.

Lymphocyte stimulation by yeast phase Histoplasma capsulatum in presumed ocular histoplasmosis syndrome

Am J Ophthalmol

(1979)

M.R Dana et al.

Prognosticators for visual outcome in sarcoid uveitis

Ophthalmology

(1996)

J.L Davis et al.

HLA associations and ancestry in Vogt–Koyanagi–Harada disease and sympathetic ophthalmia

Ophthalmology

(1990)

J.L Davis et al.

Immunocytochemical staining of vitreous cells. Indications, techniques, and results

Ophthalmology

(1992)

M.D de Smet et al.

Cellular immune responses of patients with uveitis to retinal antigens and their fragments

Am J Ophthalmol

(1990)

S Dithmar et al.

Conjunctival deposits as an initial manifestation of sarcoidosis

Am J Ophthalmol

(1999)

D.C Dumonde et al.

Anti-retinal autoimmunity and circulating immune complexes in patients with retinal vasculitis

Lancet

(1982)

R.L Font et al.

Light and electron microscopic study of Dalen-Fuchs nodules in sympathetic ophthalmia

Ophthalmology

(1983)

Criteria for diagnosis of Behçet's disease. International Study Group for Behçet's Disease

Lancet

(1990)

L.J Albert et al.

Molecular mimicry and autoimmunity

N Engl J Med

(1999)

C Althaus et al.

Intermediate uveitisepidemiology, age and sex distribution

Dev Ophthalmol

(1992)

M.R Angi et al.

Immunopathology of ocular sarcoidosis

Int Ophthalmol

(1990)

P Archambeau et al.

Posterior uveitis as a manifestation of multiple sclerosis

Mayo Clin Proc

(1965)

Ariga H, Ohno S, Higuchi M, Matsuda H: [Immunological studies on lymphocytes in the cerebrospinal fluid of patients...

E Arocker-Mettinger et al.

Intermediate uveitisdo HLA antigens play a role?

Dev Ophthalmol

(1992)

E Arocker-Mettinger et al.

Do HLA antigens play a role in intermediate uveitis?

Vox Sang

(1992)

S.B Aronson

Experimental allergic uveitis

Arch Ophthalmol

(1968)

S.B Aronson

The homoimmune uveitises in the guinea pig

Ann NY Acad Sci

(1965)

J.J Augsburger et al.

Familial pars planitis

Ann Ophthalmol

(1981)

G.S Baarsma et al.

Association of birdshot retinochoroidopathy and HLA-A29 antigen

Doc Ophthalmol

(1986)

E Baglivo et al.

Detection of anticytomegalovirus antibody synthesis in the anterior chamber in Vogt–Koyanagi–Harada syndrome

Br J Ophthalmol

(1998)

A Balboni et al.

Serological and molecular HLA typing in Italian Behçet's patientssignificant association to B51-DR5-DQw3 haplotype

Tissue Antigens

(1992)

A.S Bansal et al.

An assessment of peripheral immunity in patients with sarcoidosis using measurements of serum vitamin D3, cytokines and soluble CD23

Clin Exp Immunol

(1997)

C.G Barnes et al.

Behçet's syndrome

Rheumatology (Oxford)

(1999)

Bec P, Arne JL, Philippot V: [Basal uveo-retinitis (peripheral uveitis, chronic posterior cyclitis, pars planitis,...

M.D Becker et al.

Current and future trends in the use of immunosuppressive agents in patients with uveitis

Curr Opin Ophthalmol

(2000)

R Belfort et al.

T and B lymphocytes in the aqueous humor of patients with uveitis

Arch Ophthalmol

(1982)

BenEzra D: Histologic and immunopathologic findings in sympathetic ophthalmia. Arch Ophthalmol 103:625, 627,...

D Benezra et al.

Treatment and visual prognosis in Behçet's disease

Br J Ophthalmol

(1986)

M Berlin et al.

HLA-DR predicts the prognosis in Scandinavian patients with pulmonary sarcoidosis

Am J Respir Crit Care Med

(1997)

P.S Bhende et al.

Serological evidence for active Epstein–Barr virus infection in multifocal choroiditis

Indian J Pathol Microbiol

(1997)

A Bianco et al.

Peripheral anergy and local immune hyperactivation in sarcoidosisa paradox or birds of a feather

Clin Exp Immunol

(1997)

V Biousse et al.

Multiple sclerosis associated with uveitis in two large clinic-based series

Neurology

(1999)

J Biswas et al.

Intermediate uveitis of pars planitis type in identical twins. Report of a case

Int Ophthalmol

(1998)

E Bloch-Michel et al.

HLA antigens and uveitis with special reference to Behçet's disease, chronic herpes simplex, toxoplasmosis, and recurrent acute anterior uveitis

F Boisgerault et al.

Definition of the HLA-A29 peptide ligand motif allows prediction of potential T-cell epitopes from the retinal soluble antigen, a candidate autoantigen in birdshot retinopathy

Proc Natl Acad Sci USA

(1996)

Cited by (107)

A typical triad
2023, Revue de Medecine Interne
Ocular adverse events following vaccination: overview and update
2022, Survey of Ophthalmology
The Food and Drug Administration has licensed, approved, and expanded guidelines for dozens of vaccines since 2010. Although advancements in biotechnology have made vaccines more effective and safer, none are completely free from adverse effects. Many vaccines have been implicated in causing ocular adverse events based on the temporal association of exposure and putative complication. Determination of causality is difficult. We provide an overview of vaccine side effects and also examine the English literature and the Vaccine Adverse Events Reporting System (VAERS) from 2010 through 2020 for vaccine-implicated ocular adverse events. While reactions of eyelids and conjunctiva are commonly reported, the most frequently implicated serious adverse events are optic neuritis and various patterns of intraocular inflammation. Live attenuated vaccines have the potential to cause ocular infection from vaccine-strain organisms, particularly in those immunosuppressed. While postmarketing registries for suspect vaccination adverse events, such as VAERS, are unable to determine causal associations, they are a mainstay in signaling suspected trends that require investigation. The majority of probable and possible serious ocular adverse effects are distinctly uncommon.
Proteomic analysis of intermediate uveitis suggests myeloid cell recruitment and implicates IL-23 as a therapeutic target
2020, American Journal of Ophthalmology Case Reports
To profile vitreous protein expression of intermediate uveitis (IU) patients.
We identified a mean of 363 ± 41 unique proteins (mean ± SD) in IU vitreous and 393 ± 69 unique proteins in control samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of liquid vitreous biopsies collected during pars plana vitrectomy. A total of 233 proteins were differentially expressed among control and IU samples, suggesting a protein signature that could distinguish the two groups. Pathway analysis identified 22 inflammatory mediators of the interleukin-12 (IL-12) signaling pathway in IU vitreous. Upstream regulator analysis identified downstream mediators of IL-23 and myeloid differentiation primary response protein (MYD88), both of which are involved in the recruitment and differentiation of myeloid cells. Taken together, our results suggest the recruitment of myeloid cells as an upstream pathway in the pathogenesis of IU.
This study provides insights into proteins that will serve as biomarkers and therapeutic targets for IU. These biomarkers will help design future clinical trials using rational molecular therapeutics.
Comparative analysis of inflammatory response in the BALB/c and C57BL/6 mouse strains in an endotoxin-induced uveitis model
2020, Journal of Immunological Methods
Uveitis is an inflammatory disease associated with diverse systemic and autoimmune diseases, defined as the inflammation of any given segment of the uveal tract, uveitis contributes with 5–20% cases of blindness in the USA/Europe and >25% of cases in third-world countries. To understand its pathogenic mechanisms, BALB/c and C57BL/6 mice were induced to develop the condition by a single intraperitoneal injection of E. coli lipopolysaccharide, the aim of the present work is to determine leukocyte infiltration in an endotoxin-induced uveitis (EIU) in two non-related mouse strains. Histopathological findings and clinical analysis were conducted 24 and 48 h postinjection. Both strains presented conventional clinical signs of uveitis 24 h post LPS injection and the highest inflammatory leukocyte infiltration in the uveal tract was found in the BALB/c mouse strain. This article will give an insight on the difference of the inflammatory response in the EIU model in two different mouse strains and the relationship between the pathologic response.
Diagnostic vitrectomy: a case series in a single referral center
2019, Archivos de la Sociedad Espanola de Oftalmologia
Estudiar la eficacia y perfil de seguridad de la vitretomía diagnóstica en pacientes con uveítis no filiada.
Estudio observacional descriptivo retrospectivo de 29 pacientes (37 ojos) con panuveítis no filiada en los que se realizó vitrectomía diagnóstica. Las características clínicas y demográficas fueron recogidas. Se estudiaron los métodos de extracción de muestras y las técnicas de procesado aplicadas para el diagnóstico.
De los 29 pacientes analizados 18 (62%) eran hombres. La media de edad fue de 63,11 años (desviación estándar: 14,55). El síntoma inicial más frecuente fue la disminución de agudeza visual, la agudeza visual media fue de 20/40 excluyendo 8 ojos en los que resultó inferior a 20/200. Veintiún pacientes presentaban alteración unilateral. Se realizó extracción de muestra en seco a todos los pacientes. Además, fueron empleadas las siguientes técnicas de toma de muestras: 5 biopsias retinianas, 5 muestras diluidas, 1 aspirado de absceso subretiniano, 1 aspirado de humor acuoso. Con respecto al procesado de las muestras la técnica más utilizada fue la citología en 25 ojos, seguida de la reacción en cadena de la polimerasa en 11 ojos, el cultivo en 10 ojos. El diagnóstico etiológico fue encontrado en 94,5% de los casos, siendo el principal linfoma, seguido de toxoplasmosis.
La vitrectomía diagnóstica es útil para la identificación de la inflamación oftalmológica. Pueden utilizarse diferentes técnicas de obtención de muestras y procesado de las mismas.
To study the results and safety of diagnostic vitrectomy in patients with unknown etiology panuveitis.
A retrospective descriptive observational study was carried out in which a total of 29 patients (37 eyes) were included, who underwent a vitreous biopsy due to acute intraocular inflammatory processes. In all, demographic and clinical data were collected. We studied the specific samples extraction methods and their diagnosic processing.
Of the 29 patients analyzed, 18 were men. Mean of age was 63.11 years old (standard deviation: 14.55). The most frequent initial symptom was visual acuity decrease, with mean initial visual acuity being 20/40, excluding 8 eyes that had vision lower than 20/200. 21 presented unilateral ocular involvement. Vitrectomy was performed in all of them obtaining a dry sample.
Vitrectomy was performed in all of the patients obtaining a dry sample. Moreover, the following techniques were done: 5 retinal biopsies, obtaining 5 muestras diluidas, 1 subretinal abscess aspirate and 1 aqueous humor aspirate. The most frequent processing technique that was used was cytology in 25 eyes, followed by PCR (polymerase chain reaction) in 11 eyes and culture in 10 eyes.
Diagnosis was achieved in 94.5% of patients. Main diagnosis found was lymphoma, followed by toxoplasmosis.
Diagnostic vitrectomy is very important in ophthalmic inflammation identification. Different techniques for obtaining and processing can be used.
Ocular disease
2019, The Autoimmune Diseases
Intraocular inflammatory conditions affecting the uveal tissues and the retina are grouped under the name “uveitis.” Noninfectious forms of uveitis are referred to as “autoimmune” uveitis. The notion that autoimmune processes play a major role in these diseases is supported by the followings: (1) the diseases respond positively to treatment with immune-suppressive agents, (2) patients with uveitis show cellular and/or humoral immune responses to ocular specific antigen, and (3) pathological changes similar to those in uveitic patients are induced in experimental animals immunized with the ocular or retina-specific antigens. The animal models for uveitis, named “experimental autoimmune uveitis,” made it possible to collect information concerning the pathogenic processes that mediate the ocular disease, thus providing targets for treatment of patients.

View all citing articles on Scopus

^☆: The authors have no commercial or proprietary interest in any concept or product discussed in this article

View full text

Major reviewImmunopathology of the Noninfectious Posterior and Intermediate Uveitides☆

Abstract

Section snippets

Mechanisms of Immune Disease

Sympathetic ophthalmia

Summary

Conclusion and Future Directions

Method of Literature Search

Outline

Hum Immunol

Jpn J Ophthalmol

Clin Immunol Immunopathol

Am J Ophthalmol

Am J Ophthalmol

Semin Arthritis Rheum

Am J Ophthalmol

Am J Ophthalmol

Am J Ophthalmol

Ophthalmology

Ophthalmology

Ophthalmology

Am J Ophthalmol

Ophthalmology

Am J Ophthalmol

Ophthalmology

Ophthalmology

Ophthalmology

Am J Ophthalmol

Am J Ophthalmol

Lancet

Ophthalmology

Criteria for diagnosis of Behçet's disease. International Study Group for Behçet's Disease

Lancet

Molecular mimicry and autoimmunity

N Engl J Med

Intermediate uveitisepidemiology, age and sex distribution

Dev Ophthalmol

Immunopathology of ocular sarcoidosis

Int Ophthalmol

Posterior uveitis as a manifestation of multiple sclerosis

Mayo Clin Proc

Intermediate uveitisdo HLA antigens play a role?

Dev Ophthalmol

Do HLA antigens play a role in intermediate uveitis?

Vox Sang

Experimental allergic uveitis

Arch Ophthalmol

The homoimmune uveitises in the guinea pig

Ann NY Acad Sci

Familial pars planitis

Ann Ophthalmol

Association of birdshot retinochoroidopathy and HLA-A29 antigen

Doc Ophthalmol

Detection of anticytomegalovirus antibody synthesis in the anterior chamber in Vogt–Koyanagi–Harada syndrome

Br J Ophthalmol

Serological and molecular HLA typing in Italian Behçet's patientssignificant association to B51-DR5-DQw3 haplotype

Tissue Antigens

An assessment of peripheral immunity in patients with sarcoidosis using measurements of serum vitamin D3, cytokines and soluble CD23

Clin Exp Immunol

Behçet's syndrome

Rheumatology (Oxford)

Current and future trends in the use of immunosuppressive agents in patients with uveitis

Curr Opin Ophthalmol

T and B lymphocytes in the aqueous humor of patients with uveitis

Arch Ophthalmol

Treatment and visual prognosis in Behçet's disease

Br J Ophthalmol

HLA-DR predicts the prognosis in Scandinavian patients with pulmonary sarcoidosis

Am J Respir Crit Care Med

Serological evidence for active Epstein–Barr virus infection in multifocal choroiditis

Indian J Pathol Microbiol

Peripheral anergy and local immune hyperactivation in sarcoidosisa paradox or birds of a feather

Clin Exp Immunol

Multiple sclerosis associated with uveitis in two large clinic-based series

Neurology

Intermediate uveitis of pars planitis type in identical twins. Report of a case

Int Ophthalmol

HLA antigens and uveitis with special reference to Behçet's disease, chronic herpes simplex, toxoplasmosis, and recurrent acute anterior uveitis

Definition of the HLA-A29 peptide ligand motif allows prediction of potential T-cell epitopes from the retinal soluble antigen, a candidate autoantigen in birdshot retinopathy

Proc Natl Acad Sci USA

Major review
Immunopathology of the Noninfectious Posterior and Intermediate Uveitides☆