What is the meaning of ANCA positivity in IgG4-related disease?

OBJECTIVES: To evaluate the prevalence and meaning of antineutrophil cytoplasmic antibodies (ANCA) positivity in a cohort of IgG4-related disease (IgG4-RD). METHODS: We identified patients with ANCA determination from a retrospective cohort of 69 patients with IgG4-RD. ANCA were measured by indirect immunofluorescence microscopy (IIF) and/or proteinase 3 (PR3)-ANCA and MPO-ANCA by ELISA. IIF patterns were classified as perinuclear (P-ANCA), cytoplasmic (C-ANCA) and atypical (X-ANCA). We compared the ANCA-positive vs the ANCA-negative IgG4-RD group. RESULTS: Out of 69 patients, 31 IgG4-RD patients had an ANCA determination. Four patients with concomitant systemic autoimmune diseases were excluded. We found positive ANCA by IIF in 14 (56%) of 25 patients tested. The most common IIF pattern was C-ANCA in eight (57.1%), followed by dual C-ANCA/X-ANCA in four (28.6%) and P-ANCA and dual C-ANCA/P-ANCA in one each (7.1%). Of the 20 patients with ANCA determination by both IIF and ELISA, four have positive ANCA by ELISA (three for MPO-ANCA and one for PR3-ANCA). Of the two patients with only ELISA determination, one was positive for MPO-ANCA. The prevalence of ANCA positivity by ELISA was 22.7% (5 out of 22 patients). ANCA was more frequent in the Mikulizc/systemic phenotype (42.9%) compared with other phenotypes (P = 0.04). ANCA-positive IgG4-RD patients had more frequently lymph node and kidney involvement, high IgG1 levels and erythrocyte sedimentation rate, and positive antinuclear antibodies. CONCLUSION: ANCA are found in a significant number of patients with IgG4-RD and differed from the ANCA-negative group in terms of clinical and serological features.

Positive disease-specific autoantibodies have limited clinical significance in diagnosing IgG4-related disease in daily clinical practice.

OBJECTIVES: The 2019 ACR/EULAR classification criteria for IgG4-related disease (IgG4-RD) have exclusion criteria including positive disease-specific autoantibodies, and these have been documented to have a high specificity. This study aimed to further validate these criteria as well as identify characteristics of patients showing false-negative results. METHODS: We retrospectively analysed 162 IgG4-RD patients and 130 mimickers. The sensitivity, specificity and fulfilment rates for each criterion were calculated, and intergroup comparisons were performed to characterize the false-negative cases. RESULTS: Both the IgG4-RD patients and mimickers were aged ≥65 years with male predominance. The final diagnoses of mimickers were mainly malignancy, vasculitis, sarcoidosis and aneurysm. The classification criteria had a sensitivity of 72.8% and specificity of 100%. Of the 44 false-negative cases, one did not fulfil the entry criteria, 20 fulfilled one exclusion criterion and 27 did not achieve sufficient inclusion criteria scores. The false-negative cases had fewer affected organs, lower serum IgG4 levels, and were less likely to have received biopsies than the true-positive cases. Notably, positive disease-specific autoantibodies were the most common exclusion criterion fulfilled in 18 patients, only two of whom were diagnosed with a specific autoimmune disease complicated by IgG4-RD. In addition, compared with the true-positive cases, the 18 had comparable serum IgG4 levels, number of affected organs, and histopathology and immunostaining scores despite higher serum IgG and CRP levels. CONCLUSIONS: The ACR/EULAR classification criteria for IgG4-RD have an excellent diagnostic specificity in daily clinical practice. Positive disease-specific autoantibodies may have limited clinical significance for the diagnosis of IgG4-RD.

Unique expansion of IL-21+ Tfh and Tph cells under control of ICOS identifies Sjögren's syndrome with ectopic germinal centres and MALT lymphoma.

OBJECTIVES: To explore the relevance of T-follicular-helper (Tfh) and pathogenic peripheral-helper T-cells (Tph) in promoting ectopic lymphoid structures (ELS) and B-cell mucosa-associated lymphoid tissue (MALT) lymphomas (MALT-L) in Sjögren's syndrome (SS) patients. METHODS: Salivary gland (SG) biopsies with matched peripheral blood were collected from four centres across the European Union. Transcriptomic (microarray and quantitative PCR) analysis, FACS T-cell immunophenotyping with intracellular cytokine detection, multicolor immune-fluorescence microscopy and in situ hybridisation were performed to characterise lesional and circulating Tfh and Tph-cells. SG-organ cultures were used to investigate functionally the blockade of T-cell costimulatory pathways on key proinflammatory cytokine production. RESULTS: Transcriptomic analysis in SG identified Tfh-signature, interleukin-21 (IL-21) and the inducible T-cell co-stimulator (ICOS) costimulatory pathway as the most upregulated genes in ELS+SS patients, with parotid MALT-L displaying a 400-folds increase in IL-21 mRNA. Peripheral CD4+CXC-motif chemokine receptor 5 (CXCR5)+programmed cell death protein 1 (PD1)+ICOS+ Tfh-like cells were significantly expanded in ELS+SS patients, were the main producers of IL-21, and closely correlated with circulating IgG and reduced complement C4. In the SG, lesional CD4+CD45RO+ICOS+PD1+ cells selectively infiltrated ELS+ tissues and were aberrantly expanded in parotid MALT-L. In ELS+SG and MALT-L parotids, conventional CXCR5+CD4+PD1+ICOS+Foxp3- Tfh-cells and a uniquely expanded population of CXCR5-CD4+PD1hiICOS+Foxp3- Tph-cells displayed frequent IL-21/interferon-γ double-production but poor IL-17 expression. Finally, ICOS blockade in ex vivo SG-organ cultures significantly reduced the production of IL-21 and inflammatory cytokines IL-6, IL-8 and tumour necrosis factor-α (TNF-α). CONCLUSIONS: Overall, these findings highlight Tfh and Tph-cells, IL-21 and the ICOS costimulatory pathway as key pathogenic players in SS immunopathology and exploitable therapeutic targets in SS.

Biomarkers in Autoimmune Salivary Gland Disorders: A Review.

Salivary glands are frequent sites of manifestations of autoimmune disorders in the head and neck. Sjögren syndrome, sarcoidosis, granulomatosis with polyangiitis, and IgG4-related sialadenitis represent the most important autoimmune salivary gland disorders. Due to the lack of specific symptoms, diagnosis of these conditions remains a challenge. Diagnosis is usually based on classification criteria involving clinical tests, histopathological evaluation, and serological examinations. Depending on the disease, biomarkers are of different value and have to be interpreted carefully. In Sjögren syndrome, antibodies against Ro/SS-A and La/SS-B are essential and part of established classification criteria. In sarcoidosis, biomarkers such as angiotensin-converting enzyme, serum amyloid A, adenosine deaminase, and soluble interleukin-2 receptor are not suitable to confirm a diagnosis due to low sensitivity and specificity, but allow a differentiation between active and inactive disease. In patients with suspected granulomatosis with polyangiitis, positivity for anti-neutrophil cytoplasmic antibodies (ANCA) allows a diagnosis without histopathological confirmation in selected cases. In the head and neck, limited manifestations are common, in which less patients are positive for ANCA and histopathological confirmation is required. Diagnosis of IgG4-related sialadenitis solely based on elevated IgG4 serum levels is not possible. The concentration of blood plasmablasts is reported to have a higher diagnostic value.

CX3CL1 and CX3CR1 expression in tertiary lymphoid structures in salivary gland infiltrates: fractalkine contribution to lymphoid neogenesis in Sjogren's syndrome.

OBJECTIVES: Primary SS is an autoimmune disease characterized by chronic lymphocytic inflammation and ectopic germinal centre (GC) formation within salivary glands. Fractalkine (CX3CL1), associated with the pathogenesis of RA, is the sole member of the CX3C chemokine (CK) family and acts as an adhesion and chemotactic molecule. The objectives of this work are to determine to what extent CX3CL1 and its receptor CX3CR1 expression might be altered in salivary glands obtained from patients and to establish whether these CKs might be involved in SS ectopic lymphoneogenesis. METHODS: We assessed the presence of CX3CL1 protein in sera by ELISA in 21 patients with primary SS, 11 patients with Sicca syndrome (Sicca), 20 RA patients and 10 blood donors. Histological evaluation was performed on sequential sections of salivary gland tissue. Using TaqMan RT-PCR we studied CX3CL1 and CX3CR1 mRNA expression in salivary gland tissues from a molecular point of view. RESULTS: Increased serum levels of CX3CL1 protein were observed in SS patients compared with controls (P < 0.0001) and in RA patients compared with controls (P < 0.0001), but no difference was found between Sicca patients and controls (P = 0.22). We identified histologically the cells expressing CX3CL1 and CX3CR1 in salivary glands of SS patients and we localized the molecule within tertiary lymphoid structures. Finally, the mRNA levels of the CK and its receptor were up-regulated in SS salivary glands. CONCLUSION: We believe that our findings point to the need for future studies on CX3CL1 and CX3CR1 proteins as contributors to the formation of ectopic GCs and possibly as a new tool in the evaluation and diagnosis of SS.

Description of patients with IgG4-related disease from a Hungarian centre.

OBJECTIVES: Although most reported patients with immunoglobulin G4-related disease (IgG4-RD) are from the Far East, we aimed to identify patients suffering from IgG4-RD in our University Centre in Debrecen, Hungary. METHOD: Serum IgG4 levels were measured at 51 of our 800 patients followed up because of Sjögren's syndrome (SS) if one or more clinical signs during the disease course raised the possibility of IgG4-RD (persisting salivary gland swelling, absence of anti-Ro/SSA and anti-La/SSB antibodies in the serum, and positive salivary gland biopsy, coexistence of autoimmune pancreatitis, autoimmune hepatitis, or primary sclerosing cholangitis, persisting lymphadenopathy). Where available, histological samples of small salivary gland biopsies were revised to detect the particular features of IgG4-RD. Pathologists and surgeons were informed about the disease and asked to refer suspicious cases. RESULTS: Based on our survey, eight patients were identified with IgG4-RD. Pancreatic, salivary gland, aortic, and retroperitoneal manifestations were detected. Of the 51 patients with SS, four appeared to have IgG4-RD, but eventually one was excluded. CONCLUSIONS: Although IgG4-RD is not yet well known to physicians of Western countries, it occurs in Caucasians and probably in other races as well. Moreover, our eight cases diagnosed with IgG4-RD demonstrate a relatively large European patient population collected in a single centre. European clinicians, and especially rheumatologists, should be informed and at least certain laboratories should be prepared to investigate patient samples if the suspicion of IgG4-RD is raised. The main clinical significance of an accurate diagnosis is the extreme corticosteroid sensitivity of IgG4-RD.

Extrapancreatic findings of IgG4-related disease.

IgG4-related disease is a systemic fibro-inflammatory condition, which includes autoimmune pancreatitis as part of the disease spectrum. Imaging has been demonstrated to play a major role in the diagnosis of autoimmune pancreatitis. Recognizing the wide spectrum of extrapancreatic manifestations of IgG4-related disease coupled with a high clinical index of suspicion will allow for an accurate and timely diagnosis to be made, thus avoiding unnecessary invasive procedures and ensuring that early effective corticosteroid therapy is commenced. This review aims to serve as a concise reference tool for both clinicians and radiologists in the diagnosis of extrapancreatic IgG4-related disease.

Natural killer cells regulate murine cytomegalovirus-induced sialadenitis and salivary gland disease.

The transmission of herpesviruses depends on viral shedding at mucosal surfaces. The salivary gland represents a major site of persistent viral replication for many viruses, including cytomegalovirus. We established a mouse model of salivary gland dysfunction after acute viral infection and investigated the cellular requirements for the loss of secretion. Murine cytomegalovirus (MCMV) infection severely impaired saliva secretion independently of salivary gland virus levels. Lymphocytes or circulating monocytes/macrophages were not required for secretory dysfunction. Dysfunction occurred before glandular inflammation, suggesting that a soluble mediator initiated the disruption of acinar cell function. Despite genetic differences in innate resistance to MCMV, NK cells protected the host against acinar atrophy and the loss of secretions under conditions of an exceedingly low virus inoculum. NK cells also modulated the type of glandular inflammation after infection, as they prevented an influx of Siglec-F(+) polymorphonuclear leukocytes (PMNs). Therefore, beyond their recognized role in controlling MCMV replication, NK cells preserve organ integrity and function and regulate the innate inflammatory response within the gland.

IgG4-related disease of the head and neck.

IgG4-related disease is an uncommon sclerosing and inflammatory mass-forming disease that may affect a single organ or be systemic. The prototypical example of the disease is type 1 autoimmune pancreatitis. After the pancreatobiliary system, the head and neck is the next most common site for involvement by IgG4-related disease. Here, we describe the clinicopathologic features of the head and neck involvement by this disease process with particular attention to involvement of the major salivary glands, the lacrimal glands and periorbital tissues, the upper aerodigestive tract, the thyroid gland, lymph nodes, the ear, and the skin and soft tissues.

Localized or diffuse lesions of the submandibular glands in immunoglobulin g4-related disease in association with differential organ involvement.

OBJECTIVES: The purpose of this study was to assess the relationship between the sonographic characteristics of the submandibular glands and organ involvement at the initial presentation in patients with immunoglobulin G4 (IgG4)-related disease. METHODS: We conducted a retrospective study that included 15 patients who had bilateral swollen submandibular glands and elevated serum IgG4 levels between January 2005 and December 2010. RESULTS: In all 15 patients, sonography revealed the involvement of both sides of the submandibular glands. The sonographic appearance of each gland was classified into two types: localized tumor-forming and diffuse focal types. On the basis of this typing, all 15 patients were classified into two groups: a group with the localized tumor-forming type observed on one or both sides of the glands (n = 10) and a group with the diffuse focal type present on both sides (n = 5). All 10 patients in the former group had lesions in local exocrine organs, such as the lacrimal and parotid glands, with regional lymphadenopathy. In contrast, all 5 patients in the latter group had lesions in abdominal organs, such as autoimmune pancreatitis and sclerosing cholangitis. CONCLUSIONS: The sonographic patterns of the submandibular glands in patients with IgG4-related disease can be divided into two types: localized tumor-forming and diffuse focal. The distinctive patient groups defined by the sonographic patterns in both glands were associated with differential organ involvement and thus could be used as indicators of the disease extension and specific organ involvement.

Wegener's granulomatosis of the major salivary glands.

Wegener's granulomatosis is one of the anti-cytoplasmic autoantibodies (ANCA)-associated vasculitides. Although it typically affects the lungs and kidneys, the head and neck are also involved in most cases but the site usually affected is the upper airway. However, there are 35 cases with well-documented clinicopathological data in which Wegener's granulomatosis manifested in the major salivary glands, most commonly the parotid. Twenty-four patients presented with salivary signs and symptoms, in eight of whom there was no other presenting manifestation. These signs and symptoms may mimic infection or neoplasia and laboratory investigations, including ANCA serology and histopathology, may be non-specific; thus, in 21 of the 35 patients (60%) there was a delay in diagnosis. Amongst the 21 were 11 of the 14 (78.6%) patients who presented with unilateral parotid disease and three of the five who died. Three other patients suffered permanent pulmonary, two renal and five facial nerve damage. This article reviews the literature on major salivary gland involvement in Wegener's granulomatosis, which should be considered in the differential diagnosis of major salivary gland disease particularly if commoner causes have been excluded. A detailed medical history, and persistently inconclusive laboratory tests, could provide the clues that enable prompt diagnosis.

Radiological features of IgG4-related disease in the head, neck, and brain.

INTRODUCTION: Immunoglobulin (Ig) G4-related disease is a recently designated benign clinical entity histopathologically characterized by sclerosing inflammation and infiltration of numerous IgG4+ plasma cells that affects multiple organs. The purpose of this study is to characterize the imaging findings of patients with histopathologically proven IgG4-related disease in the head, neck, and brain. METHODS: A total of 17 patients (15 males, 2 females; mean age, 66.1 ± 7.4 years) with histopathologically proven IgG4-related disease in the head, neck, and brain were identified in two hospitals between January 2004 and December 2010. Imaging findings were retrospectively reviewed, with particular attention to the location and number of lesions, internal architecture, enhancement patterns, presence of vascular occlusion or compression, and changes in adjacent bones. RESULTS: The lesions, presented as either enlarged gland(s), or focal, localized nodules/masses, were distributed in the lacrimal gland (n = 7), the parotid gland (n = 14), the submandibular gland (n = 10), the pituitary gland (n = 2), skull base dura mater (n = 2), and the pterygopalatine fossa (n = 3). All lesions were well-defined and iso- to hypointense on T2-weighted magnetic resonance images and showed homogeneous enhancement. No lesion showed vascular occlusion or compression. Bones adjacent to the lesions showed remodeling (erosion or sclerosis) without signs of destruction (n = 6). Four patients had lesions involving multiple areas which extended along the trigeminal nerve, accompanied by expansion of neural foramina along their courses, with no signs of bone destruction. CONCLUSION: Sites of predilection for IgG4-related disease in the head, neck, and brain include the lacrimal, salivary, and pituitary glands. Recognition of the typical radiological features of IgG4-related disease, such as well-defined lesion borders, T2 hypointensity, homogeneous and gradual enhancement pattern, absence of vascular occlusion or compression, and presence of bone remodeling without destruction, may be of help in the diagnosis of this benign clinical entity.

A mouse model of autoimmune pancreatitis with salivary gland involvement triggered by innate immunity via persistent exposure to avirulent bacteria.

The pathogenesis of autoimmune pancreatitis (AIP) remains unknown. Here, we investigated the possible involvement of chronic, persistent exposure to avirulent bacteria in the pathogenesis of AIP. C57BL/6 mice were inoculated with heat-killed Escherichia coli weekly for 8 weeks. At 1 week and up to 12 months after the final inoculation, the mice were killed to obtain samples. At 1 week after the final E. coli inoculation, marked cellular infiltration with fibrosis was observed in the exocrine pancreas. Cellular infiltration in the exocrine pancreas was still observed up to 12 months after the completion of E. coli inoculation. At 10 months after the final inoculation, duct-centric fibrosis became obvious. Inflammation around the ducts in the salivary glands was also observed. Furthermore, sera from heat-killed E. coli-inoculated mice possessed anti-carbonic anhydrase, anti-lactoferrin, and antinuclear antibodies. Exposure to E. coli-triggered AIP-like pancreatitis in C57BL/6 mice. We propose a hypothetical mechanism for AIP pathogenesis. During the initiation phase, silently infiltrating pathogen-associated molecular patterns (PAMP) and/or antigen(s) such as avirulent bacteria might trigger and upregulate the innate immune system. Subsequently, the persistence of such PAMP attacks or stimulation by molecular mimicry upregulates the host immune response to the target antigen. These slowly progressive steps may lead to the establishment of AIP and associated extrapancreatic lesions. Our model might be useful for clarifying the pathogenesis of AIP.

Sicca syndrome and salivary gland infiltration in children with autoimmune disorders: when can we diagnose Sjögren syndrome?

OBJECTIVES: To analyse the initial presentation and outcome of children with a diagnosis of childhood-onset Sjögren's syndrome (SS) in a paediatric referral care center. To study whether the diagnosis was made in accordance with the most recent criteria of paediatric SS and to compare our patients to those reported in the literature. METHODS: We retrospectively analysed the clinical, histological and laboratory features of patients seen over a period of 15 years and diagnosed with SS before the age of 16. RESULTS: Eight patients had a diagnosis of SS in childhood and were followed for up to 14 years. Diagnosis of SS was based on histological evidence of salivary gland involvement in all patients with or without presence of specific autoantibodies (anti-SSA and -SSB). Sicca syndrome as a presenting symptom occurred in only 2/8 of children, recurrent parotid swelling in 3/8; whereas anti-SSA/SSB antibodies and typical salivary-gland histology were found in 6/8 patients. Five children fulfilled the proposed paediatric criteria for SS. Three patients did not fulfill the paediatric criteria but disclosed typical histology findings. Two patients developed overlapping lupus nephritis or autoimmune hepatitis years following diagnosis of SS. CONCLUSIONS: Childhood-onset SS is an heterogeneous disease in its presentation and outcome. The diagnosis may be discussed in some patients who do not fulfill the proposed diagnosis criteria, even though they disclose sicca syndrome and typical immunologic and histological findings. Some patients with typical SS may develop overlapping lupus disease over time.

Long Term Delta-9-tetrahydrocannabinol Administration Inhibits Proinflammatory Responses in Minor Salivary Glands of Chronically Simian Immunodeficieny Virus Infected Rhesus Macaques.

HIV/SIV-associated oral mucosal disease/dysfunction (HAOMD) (gingivitis/periodontitis/salivary adenitis) represents a major comorbidity affecting HIV patients on anti-retroviral therapy. Using a systems biology approach, we investigated molecular changes (mRNA/microRNA) underlying HAOMD and its modulation by phytocannabinoids (delta-9-tetrahydrocannabinol (∆9-THC)) in uninfected (n = 5) and SIV-infected rhesus macaques untreated (VEH-untreated/SIV; n = 7) or treated with vehicle (VEH/SIV; n = 3) or ∆9-THC (THC/SIV; n = 3). Relative to controls, fewer mRNAs were upregulated in THC/SIV compared to VEH-untreated/SIV macaques. Gene enrichment analysis showed differential enrichment of biological functions involved in anti-viral defense, Type-I interferon, Toll-like receptor, RIG-1 and IL1R signaling in VEH-untreated/SIV macaques. We focused on the anti-ER-stress anterior gradient-2 (AGR2), epithelial barrier protecting and anti-dysbiotic WAP Four-Disulfide Core Domain-2 (WFDC2) and glucocorticoid-induced anti-inflammatory TSC22D3 (TSC22-domain family member-3) that were significantly downregulated in oropharyngeal mucosa (OPM) of VEH-untreated/SIV macaques. All three proteins localized to minor salivary gland acini and secretory ducts and showed enhanced and reduced expression in OPM of THC/SIV and VEH/SIV macaques, respectively. Additionally, inflammation associated miR-21, miR-142-3p and miR-29b showed significantly higher expression in OPM of VEH-untreated/SIV macaques. TSC22D3 was validated as a target of miR-29b. These preliminary translational findings suggest that phytocannabinoids may safely and effectively reduce oral inflammatory responses in HIV/SIV and other (autoimmune) diseases.

Lymphocytic focus score is positively related to airway and interstitial lung diseases in primary Sjögren's syndrome.

OBJECTIVE: Although high-resolution computed tomography (HRCT) is useful for the characterization of minute morphological changes in the lungs, no study has investigated risk factors for lung involvement detected by HRCT in patients with Sjögren's syndrome with or without respiratory symptoms. The aim of the current study was to investigate risk factors for lung involvement in patients with primary Sjögren's syndrome detected by HRCT, with a particular focus on airway and interstitial lung diseases. METHODS: We performed a retrospective cohort study of patients with primary Sjögren's syndrome and investigated risk factors for lung involvement detected by HRCT. A total of 101 patients with primary Sjögren's syndrome with initial HRCT examinations were enrolled. RESULTS: Higher age, dry mouth, and higher labial gland biopsy focus scores (≥4) were risk factors for airway diseases (odds ratio [OR] 1.064 confidence interval [CI] 1.026-1.102, OR 8.795 CI 2.317-33.378 and OR 3.261 CI 1.100-9.675, respectively) in the multivariable analysis. Higher age, male sex, and higher labial gland biopsy focus scores (≥4) were risk factors for interstitial lung diseases (OR 1.078 CI 1.032-1.127, OR 12.178 CI 1.121-132.307 and OR 3.954 CI 1.423-10.987, respectively) in the multivariable analysis. The presence of anti-T-lymphotropic virus type 1 antibodies was significantly more common in patients with airway diseases. CONCLUSIONS: This study showed significant associations of labial gland biopsy focus scores and dry mouth with pulmonary manifestations in patients with primary Sjögren's syndrome. Focus scores as well as dry mouth may reflect lymphoproliferative activity in the lungs in patients with primary Sjögren's syndrome.

T and B lymphocytes in peripheral blood and tissue lesions in Sjögren's syndrome.

Lymphocyte heterogeneity was studied in peripheral blood and salivary gland lesions in 24 patients with Sjögren's syndrome. Peripheral blood B cells, measured by immunofluorescence with specific antiserum to immunoglobulins or by rosette assay with complementcoated erythrocytes, were increased in most patients. Peripheral blood T cells, measured by immunofluorescence with rabbit antiserum to human thymocytes or by rosette assay with sheep erythrocytes, were reduced in eight patients. Three had associated rheumatoid arthritis, two had a generalized lymphoproliferative disorder, and one each had scleroderma, systemic lupus erythematosus, and neuropathy. The salivary gland lymphocytic infiltrates present in labial biopsy specimens were compared in 10 patients using an indirect immunofluorescent method with anti-human T cell serum and a quantitative focus-scoring method. In general, there was a correlation between the number of T cells and the extent of the infiltrate. Striking accumulations of T cells were present in some patients, but clusters of presumed B cells were also seen. These results indicate an increase in peripheral blood B cells in most patients, a decrease in T cells in some, and a mixed T and B cell infiltrate in the salivary gland lesions.