Elevated Serum Immunoglobulin Research Articles

Elevated serum immunoglobulin E (IgE): When to suspect hyper-IgE syndrome—A 10-year pediatric tertiary care center experience

Elevated serum immunoglobulin E(IgE) can be caused by allergies, infections and immune conditions including hyper IgE syndrome (HIES). HIES is a rare primary immunodeficiency disease most commonly characterized by a triad of findings, including increased serum IgE levels, recurrent skin abscesses, and pneumonias leading to pneumatocele formation. The objective of this study was to characterize the clinical profile of patients presenting with increased IgE levels (>or=2000 IU/mL) focusing specifically on HIES. A database search identified 70 patients in the pediatric age range (<or=18 yrs.) between January 1997 and December 2006 who had an IgE level of >or=2000 IU/mL. Charts were abstracted for clinical diagnosis, comorbidities, and laboratory parameters. Data were analyzed using the students t-test, Wilcoxon signed rank test, and univariate/multivariate regression models. Clinical diagnosis in 70 patients with elevated IgE levels were: atopic diseases (n = 54; 77%), parasitic diseases (n = 1; 1.5%), malignancy (n = 2; 3%), and HIES (n = 6; 8%), among other causes. There was a statistically significant association between IgE levels and the severity of eczema (p = 0.009). Ninety percent of the subjects with IgE level >or=2000 IU/mL did not have HIES. There was no correlation between IgE levels and the diagnosis of HIES (p = 0.5). A variety of clinical situations result in an elevated IgE level, with atopy being the most common cause. In the absence of typical clinical features, elevated serum IgE levels are not predictive of HIES.

Allergic fungal sinusitis: pathophysiology, diagnosis and management

Allergic fungal sinusitis (AFS) is a noninvasive form of fungal rhinosinusitis with an incidence of between 6 and 9% of all rhinosinusitis requiring surgery. Regional variation in incidence has been reported, with the southern and southwestern US particularly endemic. Patients with AFS commonly present with chronic rhinosinusitis with nasal polyps, inhalant atopy, elevated total serum immunoglobulin E (IgE), and sinus-obstructing inspissates of a characteristic extramucosal 'peanut buttery' visco-elastic eosinophil-rich material called 'allergic mucin' that contains sparse numbers of fungal hyphae. Sinus CT is always abnormal, showing findings of chronic rhinosinusitis that often include central areas of increased contrast ('hyperattenuation') within abnormal paranasal sinuses that represent the presence of fungal-containing allergic mucin. AFS has been found to be analogous in several ways to allergic bronchopulmonary aspergillosis (ABPA). Both are chronic inflammatory respiratory tract disorders that are driven by hypersensitivity responses to the presence of small numbers of extramucosal fungi found growing within airway-impacting allergic mucin. AFS allergic mucin typically cultures positive for either dematiaceous fungi such as Bipolaris spicifera or Curvularia lunata, or Aspergillus species such as A. fumigatus, A. flavus or A. niger. As with ABPA, patients have type I immediate hypersensitivity to the etiologic mold in AFS. Further, both AFS and ABPA have been found to have association with specific class II major histocompatibility alleles. Proper diagnosis of AFS and differentiation from the other forms of both noninvasive and invasive fungal rhinosinusitis requires strict adherence to published diagnostic criteria. Medical treatment of AFS has been modeled to an extent after treatment approaches for ABPA that includes the use of postoperative oral corticosteroids and aggressive antiallergic inflammation therapy. The use of follow-up measurements of total serum IgE during treatment of both AFS and ABPA patients can help to monitor disease activity. Future AFS research will lead to further insights into pathogenesis, improved treatments, and ultimately decreases in surgical recurrence rates for this highly recurrent hypertrophic rhinosinusitis disorder.

Clinicopathological characteristics of Mikulicz's disease and K&amp;uuml;ttner's tumor

Mikulicz's disease (MD) has been considered part of primary Sjogren's syndrome (SS) since Morgan's report in 1953. However, MD shows a unique condition involving persistent swelling of the lachrymal and salivary glands characterized by good responsiveness to glucocorticoids, leading to the recovery of gland function. Recently, it has been revealed that MD patients show elevated serum immunoglobulin G4 (IgG4) concentrations and prominent infiltration of IgG4-positive plasma cells. The complications of MD include autoimmune pancreatitis, retroperotoneal fibrosis, tubulointerstitial nephritis, autoimmune hypophysitis, and Riedel's thyroiditis, all of which show IgG4 involvement in their pathogenesis. Thus, MD is a systemic IgG4-plasmacytic disease. On the other hand, Kuttner's tumor (KT) is chronic sclerosing sialadenitis that presents with asymmetrical firm swelling of the submandibular glands. Immunohistochemical analyses have revealed that a proportion of IgG4-positive plasma cells was also elevated in KT. MD and KT differ from SS and are thought to possibly form a singular systemic IgG4-related plasmacytic disease.

Kimura's Disease

Kimuras disease is a chronic inflammatory disorder of unknown etiology. It is rare in the West, but endemic in Asia. It typically presents as solitary or multiple subcutaneous nodules, that slowly increase in size. The lesions are variably painful and pruritic. It often accompanied by regional lymphadenopathy, raised serum eosinophil counts, and markedly elevated serum immunoglobulin E levels. Histologically, the lesions are characterized by reactive lymphoid follicles with eosinophilic infiltration and an increased amount of postcapillary venules. The optimal treatment for KD remains controversial. Although the condition seldom resolves spontaneously, malignant transformation has not been reported to date, and the prognosis is good. We describe a male patient with a 4-year pruritic progressive “bump” in front of his left ear. On physical examination, the patient had 2 discrete lesions on the left side of his face near his ear. Postauricularly, there was a 3 × 5 cm erythematous to violaceous, indurated nodule. Preauricularly, there was a similar, but smaller cyst-like nodule. Punch biopsy showed a superficial and deep nodular and interstitial infiltrate, reactive lymphoid follicles with a dense infiltration of eosinophils and areas of eosinophilic follicle lysis. The patient received intralesional triamcinolone acetonide injections 10 mg/cc behind left ear with a good improvement.

What Is the Prevalence of Celiac Disease Among U.S. Patients with Autoimmune Hepatitis?

Purpose: Autoimmune hepatitis (AIH) is an insidious disorder of unknown etiology, characterized by elevated serum aminotransferase and immunoglobulin G concentrations, circulating autoantibodies, lymphoplasmacytic portal and interface hepatitis and responsiveness to prednisone. Most affected European and North American AIH patients possess either the DR3 or DR4 haplotype. The hallmarks of celiac disease (CD) are gluten intolerance, and the presence of either the DR3 and/or DQ2 haplotypes. The estimated prevalence of CD in the general U.S. population is 1:100, whereas the prevalence of CD in European subjects with AIH has been estimated at between 1:16 and 1:36 in two separate studies. Therefore, we proposed to determine the prevalence of CD among patients with AIH in the U.S. Methods: We studied patients aged ≥ 18 years with a diagnosis of AIH conforming to International Autoimmune Hepatitis Group criteria, presenting at a single U.S. center between September 2003 and May 2008. Patients' sera were tested for IgA endomysial antibody (EMA) by indirect immunofluorescence; their serum IgA concentration was measured concomitantly. Patients with selective IgA deficiency (SIgAD) were tested for serum IgG gliadin antibody (AGA) by enzyme immunoassay. Results: The sample comprised 153 patients of whom 22 were male (14.4%), with a median age of 50 years (range 18–81). The ethnic distribution was: 115 (75.2%) Caucasian, 33 (21.6%) African American non-Hispanic, two (1.3%) native American, two (1.3%) Asian, and one (0.6%) Caucasian Hispanic. One patient had a positive EMA result (duodenal mucosal biopsies were consistent with CD). One man had selective IgA deficiency, but his AGA IgG titer was normal (5.1 units: normal 0–25). Five women underwent endoscopic duodenal mucosal biopsy despite negative EMA results (four had iron deficiency anemia, the other loose stools and weight loss). One patient demonstrated histological findings consistent with CD, whereas the other four demonstrated normal histology. Conclusion: Although the prevalence of CD in these U.S. patients with AIH (1:76 [1.3%]) is considerably less than reported among European AIH patients, it is slightly greater than in the general U.S. population. This suggests the possibility of increased risk for CD among U.S. patients with AIH, and therefore appropriate serologic screening. Conversely, the study sample may have been underpowered, thereby resulting in findings which suggest a difference that does not truly exist. In either case, it appears that EMA may not be the most appropriate screening test for CD in AIH patients: only one of the two patients identified with CD in this group yielded a positive antibody result.

Non-episodic angioedema associated with eosinophilia following Mycoplasma pneumoniae infection

Episodic angioedema with eosinophilia is characterized by recurrent angioedema, peripheral eosinophilia, fever, weight gain, elevated serum immunoglobulin M (IgM), and a benign course lacking any internal organ involvement. A non-episodic variant has also been reported which is limited to a single attack and normally is less severe than the episodic type. We report a case of Mycoplasma pneumoniae infection with dermatological manifestation that was followed by non-episodic angioedema with eosinophilia including fever, weight gain, and elevated serum IgM. Even though the patient's clinical characteristics resemble episodic angioedema with eosinophilia as reported by Gleich, angioedema was non-episodic. This may be due to systemic corticosteroid treatment which was prescribed because of persistent skin manifestation following M. pneumoniae infection. The current report is the first observation suggesting that angioedema associated with eosinophilia may be triggered by atypical bacterial infection.

Churg–Strauss syndrome with peripheral gangrene and severe renal failure

ABSTRACTA 32‐year‐old man, known asthmatic since childhood, presented with multiple ulcers over lower legs, burning sensation over fingers and blackish discoloration of left little finger. On examination, he had systemic hypertension, tenderness over maxillary sinuses, left‐sided foot drop and gangrene of left little finger. The investigations showed anemia, eosinophilia, elevated serum immunoglobulin E level, elevated myeloperoxidase level, proteinuria and raised creatinine. A diagnosis of Churg‐Strauss syndrome with rare manifestations of gangrene and severe renal failure was made with the above features.

Multiple Myeloma Cancer Stem Cells

Multiple myeloma is characterized by the clonal expansion of neoplastic plasma cells within the bone marrow, elevated serum immunoglobulin, and osteolytic bone disease. The disease is highly responsive to a wide variety of anticancer treatments including conventional cytotoxic chemotherapy, corticosteroids, radiation therapy, and a growing number of agents with novel mechanisms of action. However, few if any patients are cured with these modalities and relapse remains a critical issue. A better understanding of clonogenic multiple myeloma cells is essential to ultimately improving long-term outcomes, but the nature of the cells responsible for myeloma regrowth and disease relapse is unclear. We review evidence that functional heterogeneity exists in multiple myeloma and discuss potential strategies and clinical implications of the stem-cell model of cancer in this disease.

Traffic-Related Outdoor Air Pollution and Respiratory Symptoms in Children

Outdoor concentrations of soot and nitrogen dioxide (NO2) outside of schools have been associated with children's respiratory and eye symptoms. We assessed how adjustments for measurement error affect these associations. Concentrations of air pollutants outside children's schools were validated by personal measurements of exposure to traffic-related air pollution. We estimated prevalence ratios of 4 health outcomes (current wheeze, conjunctivitis, phlegm, and elevated total serum immunoglobulin E) using school outdoor measurements, and then adjusted for measurement error using the personal exposure data and applying a regression calibration method. The analysis adjusting for measurement error was carried out using a main study/external validation design. Adjusting for measurement error produced effect estimates related to soot and NO2 that were 2 to 3 times higher than in the original study. The adjusted prevalence ratio for current phlegm was 5.3 (95% confidence interval = 1.2-23) for a 9.3 microg/m3 increase in soot, and 3.8 (1.0-14), for a 17.6 microg/m3 increase in NO2, compared with the original results of 2.2 (1.3-3.9) and 1.8 (1.1-2.8), respectively. Corrections were of similar magnitude for the prevalence of current wheeze, current conjunctivitis, and total elevated total immunoglobulin E. The estimated effects of outdoor air pollution on respiratory and other health effects in children may be substantially attenuated when based on exposure measurements outside schools instead of personal exposure.

Eosinophilic ascites

A 37-year-old Chinese man was admitted with nausea, vomiting and progressive abdominal distension for 10 days. He had a history of adult-onset bronchial asthma for 2 years. Physical examination revealed an obvious shifting dullness. Laboratory studies showed leukocyte count 24.56×109/l with 53% eosinophils and normal liver and renal functions. Searching for autoimmune disorders or malignancy only yielded elevated serum immunoglobulin E (498IU/ml, normal <165IU/ml). Abdominal ultrasonography demonstrated massive ascites without hepatosplenomegaly.

Kimura’s disease—an unusual cause of lymphadenopathy in children

Kimura's disease is a rare inflammatory disorder of unknown cause primarily seen in young Asian males. The disease is characterized by a triad of painless subcutaneous masses in the head or neck region, blood and tissue eosinophilia, and markedly elevated serum immunoglobulin E levels. We describe a 3-year-old Indian boy with Kimura's disease who presented with generalized lymphadenopathy. The diagnosis was based on the characteristic histopathologic findings after surgical excision in conjunction with peripheral eosinophilia and elevated serum immunoglobulin E levels.

Serum immunoglobulin G fraction 4 levels in pancreatic cancer: elevations not associated with autoimmune pancreatitis.

Abstract Context.—Autoimmune pancreatitis is an uncommon, inflammatory disease of the pancreas that presents with clinical features, such as painless jaundice and a pancreatic mass, similar to those caused by pancreatic cancer. Patients with autoimmune pancreatitis frequently have elevated serum immunoglobulin G fraction 4 (IgG4) levels, and their pancreatic tissue may show IgG4-positive plasma cell infiltration. It is imperative to differentiate autoimmune pancreatitis from pancreatic cancer because autoimmune pancreatitis typically responds to corticosteroid treatment. A previous Japanese study reported that serum IgG4 greater than 135 mg/dL was 97% specific and 95% sensitive in predicting autoimmune pancreatitis. Objective.—To prospectively measure serum IgG4 levels in pancreatic cancer patients to ascertain whether increased levels might be present in this North American population. Design.—We collected blood samples and phenotypic information on 71 consecutive pancreatic cancer patients and 103 healt...

Serum Immunoglobulin G Fraction 4 Levels in Pancreatic Cancer: Elevations Not Associated With Autoimmune Pancreatitis

Autoimmune pancreatitis is an uncommon, inflammatory disease of the pancreas that presents with clinical features, such as painless jaundice and a pancreatic mass, similar to those caused by pancreatic cancer. Patients with autoimmune pancreatitis frequently have elevated serum immunoglobulin G fraction 4 (IgG4) levels, and their pancreatic tissue may show IgG4-positive plasma cell infiltration. It is imperative to differentiate autoimmune pancreatitis from pancreatic cancer because autoimmune pancreatitis typically responds to corticosteroid treatment. A previous Japanese study reported that serum IgG4 greater than 135 mg/dL was 97% specific and 95% sensitive in predicting autoimmune pancreatitis. To prospectively measure serum IgG4 levels in pancreatic cancer patients to ascertain whether increased levels might be present in this North American population. We collected blood samples and phenotypic information on 71 consecutive pancreatic cancer patients and 103 healthy controls who visited our clinics between October 2004 and April 2006. IgG4 levels were determined using a single radial immunodiffusion assay. A serum IgG4 level greater than 135 mg/dL was considered elevated. Five cancer patients had IgG4 elevation, with a mean serum IgG4 level of 160.8 mg/dL. None of our cancer patients with plasma IgG4 elevation demonstrated evidence of autoimmune pancreatitis. One control subject demonstrated elevated serum IgG4 unrelated to identified etiology. As many as 7% of patients with pancreatic cancer have serum IgG4 levels above 135 mg/dL. In patients with pancreatic mass lesions and suspicion of cancer, an IgG4 level measuring between 135 and 200 mg/dL should be interpreted cautiously and not accepted as diagnostic of autoimmune pancreatitis without further evaluation.

Thrombosis of temporal artery and renal vein in Kimura disease related nephrotic syndrome

Kimura disease (KD) is an angiolymphoid proliferative disorder of unknown etiology, occurs mainly in Asian patients, presenting with subcutaneous slowly growing masses, with a predilection for preauricular and submandibular regions. The clinical course of the disease is thought to be benign. Concomitant peripheral blood eosinophilia and elevated serum immunoglobulin E levels are often observed. Main systemic manifestation of the KD is renal involvement. Renal abnormalities, notably proteinuria and nephrotic syndrome have been found to be associated with KD. We report a 42-year-old man with KD and a steroid-sensitive membraneous nephrotic syndrome with bilaterally temporal artery and renal vein thrombosis. This is the first reported case of KD associated nephrotic syndrome complicated with wide arterial and venous thrombosis from Anatolia.

Hyperimmunoglobulin E syndrome and tyrosine kinase 2 deficiency

The purpose of the review is to provide recent insight into the pathogenesis and pathophysiology of hyperimmunoglobulin E syndrome. We recently identified a homozygous four base-pair deletion in the coding region of the tyrosine kinase 2 gene in a hyperimmunoglobulin E syndrome patient who exhibited susceptibility to intracellular bacteria. Hyperimmunoglobulin E syndrome is a primary immunodeficiency characterized by recurrent staphylococcal skin abscesses and pneumonia, and elevated serum immunoglobulin E. This syndrome is subdivided into types 1 and 2. Type 1 displays abnormalities in multiple systems, including the skeletal/dental and immune systems, whereas type 2 abnormalities are confined to the immune system. We recently identified a homozygous mutation in the tyrosine kinase 2 gene in a type 2 patient. Analyses of cytokine responses in the patient's cells revealed that the tyrosine kinase 2 deficiency had resulted in severe impairment of the signal transduction for multiple cytokines, including interleukin-6, -10, -12 and -23, and interferon-alpha/beta. The cytokine signals were successfully restored by transducing the intact tyrosine kinase 2 gene. Thus, tyrosine kinase 2 plays obligatory roles in human immunity. Based on this finding, we propose that hyperimmunoglobulin E syndrome is a primary immunodeficiency caused by genetic alterations leading to the defect in multiple cytokine signals.

Association of respiratory complications and elevated serum immunoglobulins with drinking water arsenic toxicity in human

We assessed the relationship between chronic arsenic exposure through drinking water with respiratory complications and humoral immune response by measuring serum immunoglobulin profiles in the affected subjects (arsenicosis patients) living in the arsenic endemic rural villages of Bangladesh. The duration of exposure was determined through detailed history of the patients (n = 125) and the levels of arsenic in the drinking water and urine samples were determined. The mean duration of exposure in the patients was 7.4 ± 5.3 y, and the levels of arsenic in the drinking water and urine samples were 216 ± 211 and 223 ± 302 μ g/L, respectively, compared to 11 ± 20 and 29 ± 19 μ g/L, respectively, in the unexposed subjects. There was high prevalence of respiratory complications like breathing problems including chest sound, asthma, bronchitis and cough associated with drinking water arsenic toxicity. Arsenicosis patients had significantly elevated levels of IgG (P < 0.001) and IgE (P < 0.001) while the levels of IgA were also significantly higher (P < 0.005) but IgM were similar to that of the control subjects. Analysis of the clinical symptoms based on skin manifestations showed the levels of both IgG and IgE were significantly elevated during the initial stages while IgE were further elevated with the duration of arsenic exposure. Arsenicosis patients with respiratory complications had mean serum IgE levels of 706 ± 211 IU/mL compared to 542 ± 241 IU/mL in patients without apparent involvement with the respiratory system (P < 0.01). The eosinophil counts in the patients did not differ significantly from the unexposed subjects indicating that elevated levels of serum IgE might not be due to allergic diseases, rather it could be due to direct effects of arsenic. We found significant linear relationships between the levels of serum IgE and inorganic phosphorus (P < 0.05), and serum IgA levels with urinary excretion of arsenic (P < 0.001). These observations suggested that arsenic toxicity caused respiratory complications, induced changes in the humoral as well as mucosal immune responses.

Role of X chromosome defects in primary biliary cirrhosis

Similar to the majority of autoimmune conditions, primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by a striking female predominance; it is characterized by high titer serum autoantibodies to mitochondrial antigens, elevated serum immunoglobulin M, progressive destruction of intrahepatic bile ducts, and ultimately liver cirrhosis and failure. Familiarity and high concordance rates for the disease among monozygotic twins strongly support the role of genetics in the disease. Experimental efforts have been dedicated by our and other research groups to investigate the role of X chromosome abnormalities (i.e. monosomyrates and inactivation patterns) in autoimmunity. Our recent work has demonstrated enhanced X monosomy in women with PBC as well as two other female-predominant autoimmune diseases, systemic sclerosis and autoimmune thyroid disease. We will review herein the most recent evidence on the role of the X chromosome in PBC onset and discuss the potential implications. Future developments of these findings will be discussed.

Repression of interleukin-4 in T helper type 1 cells by Runx/Cbfβ binding to the Il4 silencer

Interferon γ (IFNγ) is the hallmark cytokine produced by T helper type 1 (Th1) cells, whereas interleukin (IL)-4 is the hallmark cytokine produced by Th2 cells. Although previous studies have revealed the roles of cytokine signaling and of transcription factors during differentiation of Th1 or Th2 cells, it is unclear how the exclusive expression pattern of each hallmark cytokine is established. The DNaseI hypersensitivity site IV within the mouse Il4 locus plays an important role in the repression of Il4 expression in Th1 cells, and it has been named the Il4 silencer. Using Cbfβ- or Runx3-deficient T cells, we show that loss of Runx complex function results in derepression of IL-4 in Th1 cells. Binding of Runx complexes to the Il4 silencer was detected in naive CD4+ T cells and Th1 cells, but not in Th2 cells. Furthermore, enforced expression of GATA-3 in Th1 cells inhibited binding of Runx complexes to the Il4 silencer. Interestingly, T cell–specific inactivation of the Cbfβ gene in mice led to elevated serum immunoglobulin E and airway infiltration. These results demonstrate critical roles of Runx complexes in regulating immune responses, at least in part, through the repression of the Il4 gene.

B Cell-Specific Deletion of Protein-Tyrosine Phosphatase Shp1 Promotes B-1a Cell Development and Causes Systemic Autoimmunity

Spontaneous loss-of-function mutations in the protein-tyrosine phosphatase Shp1 cause the motheaten phenotype, characterized by widespread inflammation and autoimmunity. Because Shp1 is expressed in all hematopoietic cells, it has been unclear which aspects of the motheaten phenotypes are primary effects of Shp1 deficiency. We generated mice (Ptpn6(f/f);CD19-cre) that delete Shp1 specifically in B cells. Analysis of these mice indicates that the increase in B-1a cells in motheaten mice is a cell-autonomous consequence of Shp1 deficiency. Shp1-deficient B-1a cells could be derived from adult bone marrow and had N-nucleotide additions, consistent with an adult origin. Shp1 deficiency altered calcium response evoked by B cell antigen receptors and impaired CD40-evoked proliferation. Young Ptpn6(f/f);CD19-cre mice exhibited elevated serum immunoglobulins and impaired antibody responses to immunization, whereas older Ptpn6(f/f);CD19-cre mice developed systemic autoimmunity, characterized by DNA antibodies and immune complex glomerulonephritis. Thus, Shp1 deficiency in B cells alone perturbs B cell development and causes autoimmune disease.

Cross‐reactive adaptive immune response to oral commensal bacteria results in an induction of receptor activator of nuclear factor‐κB ligand (RANKL)‐dependent periodontal bone resorption in a mouse model

The present study examined whether induction of an adaptive immune response to orally colonizing non-pathogenic Pasteurella pneumotropica by immunization with the phylogenetically closely related bacterium, Actinobacillus actinomycetemcomitans, can result in periodontal bone loss in mice. BALB/c mice harboring P. pneumotropica (P. pneumotropica(+) mice) in the oral cavity or control P. pneumotropica-free mice were immunized with fixed A. actinomycetemcomitans. The animals were sacrificed on day 30, and the following measurements were carried out: (i) serum immunoglobulin G and gingival T-cell responses to A. actinomycetemcomitans and P. pneumotropica; (ii) periodontal bone loss; and (iii) identification of receptor activator of nuclear factor-kappaB ligand (RANKL) -positive T cells in gingival tissue. Immunization with A. actinomycetemcomitans induced a significantly elevated serum immunoglobulin G response to the 29-kDa A. actinomycetemcomitans outer membrane protein (Omp29), which showed strong cross-reactivity with P. pneumotropica OmpA compared to results in the control non-immunized mice. The A. actinomycetemcomitans-immunized P. pneumotropica(+) mice developed remarkable periodontal bone loss in a RANKL-dependent manner, as determined by the abrogation of bone loss by treatment with osteoprotegerin-Fc. The T cells isolated from the gingival tissue of A. actinomycetemcomitans-immunized P. pneumotropica(+) mice showed an in vitro proliferative response to both A. actinomycetemcomitans and P. pneumotropica antigen presentation, as well as production of soluble(s)RANKL in the culture supernatant. Double-color confocal microscopy demonstrated that the frequency of RANKL(+) T cells in the gingival tissue of A. actinomycetemcomitans-immunized P. pneumotropica(+) mice was remarkably elevated compared to control mice. The induction of an adaptive immune response to orally colonizing non-pathogenic P. pneumotropica results in RANKL-dependent periodontal bone loss in mice.