Secretory IgA Deficiency Research Articles

Monocyte-derived dendritic cells link localized secretory IgA deficiency to adaptive immune activation in COPD

Although activation of adaptive immunity is a common pathological feature of chronic obstructive pulmonary disease (COPD), particularly during later stages of the disease, the underlying mechanisms are poorly understood. In small airways of COPD patients, we found that localized disruption of the secretory immunoglobulin A (SIgA)-containing mucosal immunobarrier correlated with lymphocyte accumulation in airway walls and development of tertiary lymphoid structures (TLS) around small airways. In SIgA-deficient mice, we observed bacterial invasion into the airway epithelial barrier with lymphocytic infiltration and TLS formation, which correlated with the progression of COPD-like pathology with advanced age. Depletion of either CD4+ or CD8+ T lymphocytes reduced the severity of emphysema in SIgA-deficient mice, indicating that adaptive immune activation contributes to progressive lung destruction. Further studies revealed that lymphocyte infiltration into the lungs of SIgA-deficient mice was dependent on monocyte-derived dendritic cells (moDCs), which were recruited through a CCR2-dependent mechanism in response to airway bacteria. Consistent with these results, we found that moDCs were increased in lungs of COPD patients, along with CD4+ and CD8+ effector memory T cells. Together, these data indicate that endogenous bacteria in SIgA-deficient airways orchestrate a persistent and pathologic T lymphocyte response through monocyte recruitment and moDC differentiation.

A Rare Case of Secretory IgA Deficiency causing Chronic Sialadenitis

Introduction: To share a rare case of secretory IgA deficiency causing chronic sialadenitis and discuss it's learning points.

Secretory IgA Deficiency in Individual Small Airways Is Associated with Persistent Inflammation and Remodeling.

Maintenance of a surface immune barrier is important for homeostasis in organs with mucosal surfaces that interface with the external environment; however, the role of the mucosal immune system in chronic lung diseases is incompletely understood. We examined the relationship between secretory IgA (SIgA) on the mucosal surface of small airways and parameters of inflammation and airway wall remodeling in chronic obstructive pulmonary disease (COPD). We studied 1,104 small airways (<2 mm in diameter) from 50 former smokers with COPD and 39 control subjects. Small airways were identified on serial tissue sections and examined for epithelial morphology, SIgA, bacterial DNA, nuclear factor-κB activation, neutrophil and macrophage infiltration, and airway wall thickness. Morphometric evaluation of small airways revealed increased mean airway wall thickness and inflammatory cell counts in lungs from patients with COPD compared with control subjects, whereas SIgA level on the mucosal surface was decreased. However, when small airways were classified as SIgA intact or SIgA deficient, we found that pathologic changes were localized almost exclusively to SIgA-deficient airways, regardless of study group. SIgA-deficient airways were characterized by (1) abnormal epithelial morphology, (2) invasion of bacteria across the apical epithelial barrier, (3) nuclear factor-κB activation, (4) accumulation of macrophages and neutrophils, and (5) fibrotic remodeling of the airway wall. Our findings support the concept that localized, acquired SIgA deficiency in individual small airways of patients with COPD allows colonizing bacteria to cross the epithelial barrier and drive persistent inflammation and airway wall remodeling, even after smoking cessation.

A Hairline Crack in the Levee: Focal Secretory IgA Deficiency as a First Step toward Emphysema.

A Hairline Crack in the Levee: Focal Secretory IgA Deficiency as a First Step toward Emphysema.

The Journal Club: COPD Exacerbations

In this issue, I review articles that provide further insights into the pathogenesis and/or management of chronic obstructive pulmonary disease (COPD) exacerbations. Exacerbations remain a significant source of cost, morbidity and progression of disease. The current Global initiative for chronic Obstructive Lung Disease (GOLD) guidelines1 focus on symptoms and exacerbations as the major factors to consider in treatment escalation. In the earlier editions of COPD recommendations and guidelines, inhaled corticosteroids (ICSs) have played a central role in dealing with acute exacerbations. The most recent iteration of the (GOLD) guidelines suggests that long-acting muscarinic antagonists (LAMAs) are first line therapy for patients with a history of 2 or more exacerbations in the previous 12 months. If these fail then a combination with a long-acting beta-agonist (LABA) is recommended. The recommendation to try LAMAs or a LABA/LAMA combination before an ICS/LABA combination for treatment of exacerbations appears to be related in large part to evidence that there may be an increased risk of pneumonia with use of inhaled corticosteroids for at least some COPD patients. In the last Journal Club, I highlighted that there remains an ongoing debate with regard to whether there is a subset of patients for whom ICS/LABAs may be a preferred first choice. The first paper presented in this Journal Club, the TRINITY Trial, compares a new triple combination ICS/LABA/LAMAs versus the use of LAMA alone for prevention of COPD exacerbations. The second paper reviewed is the most recent American Thoracic Society/European Respiratory Society guidelines for treatment of acute exacerbations. It provides a thorough review of the literature regarding the evidence for some of the most common practices in the treatment of acute exacerbations, from use of oral steroids and antibiotics to in-home management with non-invasive ventilation. Finally, I have included an interesting paper that examines the potential role of secretory IgA deficiency in select small airways as a potential pathogenic mechanism for persistent small airway inflammation and reinfection in patients with frequent COPD exacerbations.

Bronchial secretory immunoglobulin a deficiency correlates with airway inflammation and progression of chronic obstructive pulmonary disease.

Although airway inflammation can persist for years after smoking cessation in patients with chronic obstructive pulmonary disease (COPD), the mechanisms of persistent inflammation are largely unknown. We investigated relationships between bronchial epithelial remodeling, polymeric immunoglobulin receptor (pIgR) expression, secretory IgA (SIgA), airway inflammation, and mural remodeling in COPD. Lung tissue specimens and bronchoalveolar lavage were obtained from lifetime nonsmokers and former smokers with or without COPD. Epithelial structural changes were quantified by morphometric analysis. Expression of pIgR was determined by immunostaining and real-time polymerase chain reaction. Immunohistochemistry was performed for IgA, CD4 and CD8 lymphocytes, and cytomegalovirus and Epstein-Barr virus antigens. Total IgA and SIgA were measured by ELISA and IgA transcytosis was studied using cultured human bronchial epithelial cells. Areas of bronchial mucosa covered by normal pseudostratified ciliated epithelium were characterized by pIgR expression with SIgA present on the mucosal surface. In contrast, areas of bronchial epithelial remodeling had reduced pIgR expression, localized SIgA deficiency, and increased CD4(+) and CD8(+) lymphocyte infiltration. In small airways (<2 mm), these changes were associated with presence of herpesvirus antigens, airway wall remodeling, and airflow limitation in patients with COPD. Patients with COPD had reduced SIgA in bronchoalveolar lavage. Air-liquid interface epithelial cell cultures revealed that complete epithelial differentiation was required for normal pIgR expression and IgA transcytosis. Our findings indicate that epithelial structural abnormalities lead to localized SIgA deficiency in COPD airways. Impaired mucosal immunity may contribute to persistent airway inflammation and progressive airway remodeling in COPD.

Duodenal nodularity in children: A clinical and pathologic study of 17 cases

Duodenal nodularity is an uncommon endoscopic appearance of numerous visible mucosal nodules in the proximal duodenum. In this retrospective study we aimed to determine the clinical significance and histopathologic features of duodenal nodularity in children. The medical records of the patients who were defined to have duodenal nodularity by endoscopy were reviewed. The data were expressed as mean ± SD and percentages (%). Seventeen patients with endoscopically defined duodenal nodularity were chosen. The mean age at diagnosis was 12.1 years (range: 6-17 years), 9 males. Abdominal pain (47%) was the most common clinical symptom and antral nodularity (41%) was the most common endoscopic finding in children with duodenal nodularity. Histopathologic evaluation of duodenal nodules revealed chronic inflammation in all patients, increased intercryptal and intraepithelial numbers of eosinophils in 70.5%, and villous atrophy in 47% of patients. Giardia infestation was demonstrated in 6 patients by histologic examination and/or Giardia lamblia-specific antigen positivity in stools. The clinical diagnoses of the patients have shown variations, such as celiac disease, giardiasis, secretory IgA deficiency, and Helicobacter pylori gastritis, and some of them were associated with the others. Although the endoscopic appearance is similar, clinical spectrum and pathologic features are not so similar and there are no specific histomorphologic findings for nodularity. The most demonstrative findings we observed in children were increased lymphocyte and/or eosinophil infiltration in the duodenal mucosa. We suggested that care should be taken in the evaluation of microbiological and immunologic etiologies causing this prominent inflammatory reaction.

Epithelial Changes in Seasonal Allergic Rhinitis throughout the Year: Evidence of Coexistent Air Pollution and Local Secretory IgA Deficiency?

To determine possible epithelial changes in seasonal allergic rhinitis, we examined epithelial cells in cytology swab preparations of 38 non-smoking patients, exclusively sensitized to grass pollen, throughout the year, and surgical material of 8 patients. Cytologically, we found a marked goblet cell hyperplasia during the period of grass pollen exposure, while meta- and dysplasia were found throughout the year. Immunohistochemically, a lack of secretroy IgA in the altered epithelium was detected. These results were not obtained in the control group of 60 healthy non-smokers. Since we have recently found the same epithelial changes of meta- and dysplasia in smokers, these findings may point to non-specific toxic damage of the nasal epithelium possibly caused by other air pollutants. The altered epithelium may lead to an impairment of the local secretory IgA defence system and thereby to an increased allergen uptake.

Transient secretory IgA deficiency in mice after cyclophosphamide treatment

Cyclophosphamide (Cy), an alkylating agent widely used in chemotherapy of leukemia and cancer, causes a well-documented toxicity on hematopoietic and lymphoid cells. Neutropenia is thought to be the main factor involved in infectious complications following antimitotic chemotherapy. Little is known on the effects of these therapies on the mucosal associated lymphoid system which is one of the main barriers against environmental pathogenic agents. The present study examined the effects of a single administration of Cy (200 mg/kg) on murine T and B cell populations of Peyer's patches (PPs), IgA secretion in the proximal part of the small intestine, and plasma cells of the lamina propria. Cy induced in mice a transient decrease in the T and B cell populations of the PPs with a drastic fall of B cell counts and a profound decrease of intestinal IgA secretion due to a reduction of lamina propria plasma cells. This transient secretory IgA deficiency may contribute to the infectious complications following antimitotic chemotherapy.

Secretory immunoglobulin a in urinary tract infection, chronic glomerulonephritis, and renal transplantation

An enzyme-linked immunoassay (ELISA) for the quantitation of secretory IgA (S-IgA) in the urine is described. The assay is sensitive (linear down to 0.02 μg/ml), specific, and reproducible (intraassay variation 7.8%, interassay variation 18.9%). The assay was used to determine the urinary excretion rates of S-IgA in patients with bladder catheter ( n = 12), cystotomy and urinary tract infection ( n = 13), urosepsis ( n = 5), chronic glomerulonephritis, including IgA-nephritis ( n = 31), in renal allograft recipients ( n = 30), and in healthy controls ( n = 46). An elevated S-IgA urinary excretion ( P < 0.01) was found in all patient groups studied. The highest values were observed in urosepsis. No significant differences between S-IgA levels in IgA-nephritis and other forms of chronic glomerulonephritis were detected. The elevated S-IgA excretion in renal allograft recipients indicates that immunosuppressive therapy does not influence the local S-IgA production in the urinary tract. The susceptibility of these patients to urinary tract infections is therefore not due to a S-IgA deficiency.

The wasted mutant mouse. I. An animal model of secretory IgA deficiency with normal serum IgA.

The wasted (wst) mutation was recently described as a spontaneous, recessive mutation leading to pathologic changes affecting both the neurologic and the immune systems of wst/wst homozygotes, which presented symptoms analogous to those observed in patients with ataxia-telangiectasia (A.T.). We studied the IgA system of wst/wst mutants and their normal littermates to determine whether IgA deficiency commonly found in A.T. patients was also affecting these mutants. Interestingly, although IgA plasma cells were totally absent from their entire (small and large) intestine, their serum contained a normal level of IgA with a normal ratio of monomeric vs polymeric IgA. The absence of gut IgA plasma cells was not due to malnutrition and was not compensated by the appearance of cells secreting any other isotypes. Studies at the precursor cell level showed the absence of IgA-specific B cell precursors in the Peyer's patches, whereas sIgA B cells and IgA plasma cells were found in normal numbers in the spleen of wasted mice. These data suggest that secretory and serum IgA may comprise distinct systems and that the wasted mutant mouse is a potential model for the study of the physiology and regulation of IgA production.

Gastrointestinal complications of congenital immunodeficiency states. The surgeon's role.

Ninety-one congenitally immunodeficient patients treated from 1972 to 1981 were reviewed to assess the incidence and nature of gastrointestinal complications. Thirty-three of these patients (36%) developed 59 complications. Patients with immunodeficiencies characterized by neutrophil dysfunction--chronic granulomatous disease (20 patients) and cyclic neutropenia (eight patients)--developed 22 surgical infections, 22 of which required operation. In patients with neutrophil defects, postoperative morbidity was frequent and severe. Gastrointestinal symptoms were common in patients with isolated defects of B or T lymphocytes. Ten of forty-one patients with congenital hypogammaglobulinemia developed gastrointestinal complications, as did one of four patients with DiGeorge Syndrome, and the single patient with secretory IgA deficiency. However, operation was not required for these patients with isolated disorders of lymphocyte function. Patients with combined B and T cell disorders developed gastrointestinal disease, requiring operative therapy at intermediate rates. Gastrointestinal symptoms developed in four of nine patients with severe combined immunodeficiency and three of eight with Wiskott-Aldrich syndrome. Operative therapy was required in two of these seven symptomatic patients.

Disordered salivary immunoglobulin secretion and sodium transport in human chronic graft-versus-host disease.

Whole saliva samples and lip biopsies were collected from 12 allogeneic bone marrow transplant recipients who developed extensive chronic graft-versus-host disease (GVHD) and from 10 healthy allogeneic and syngeneic recipients without GVHD. Six of ten biopsies from patients with chronic GVHD had lichenoid stomatitis or sialadenitis, or both, with sialodochitis. Seven of nine biopsies from patients free of chronic GVHD were entirely normal, and two had either mild glandular or mucosal changes. Salivary gland involvement in chronic GVHD was associated with decreased or absent levels of salivary IgA and inorganic phosphate, decreased salivary flow rates, and increased concentrations of salivary sodium, albumin, and IgG. The most striking abnormalities were found in patients with histologic evidence of sialadenitis. In contrast, marrow transplant recipients without chronic GVHD had normal salivary immunoglobulin and electrolyte levels. Secretory IgA deficiency may contribute to the frequent sinobronchial infections observed in patients with chronic GVHD.

Serum and Salivary IgA Levels in Normal Subjects: Comparison between Tonsillectomized and Non-Tonsillectomized Subjects

Serum IgA and secretory IgA (SIgA) were determined in 1,000 apparently healthy subjects; 274 were tonsillectomized. Four groups were identified in this study: (1) 0.3% of subjects had no serum IgA and SIgA; (2) 1.6% of subjects showed partial serum and SIgA deficiency; (3) 27.4% of individuals were tonsillectomized and had partial serum IgA deficiency but normal SIgA, and (4) 71.4% were normal, both with respect to serum IgA and SIgA. There results stress the relatively high incidence of IgA deficiency in the normal population and confirm the role of the tonsils in maintaining serum IgA levels.

Giardiasis: a common cause of diarrheal disease.

Giardiasis has been reported increasingly among visitors to the Soviet Union and is found at epidemic and endemic levels in the United States. The main source of infection is contaminated water. Children, homosexual males, and patients with gastrectomy, achlorhydria, hypogammaglobulinemia, secretory IgA deficiency, or alteration in immune status are particularly susceptible to severe, often chronic, infection. Symptomatic giardiasis can be acute, subacute, or chronic. Symptoms are explosive, watery, foul-smelling stools or semisolid stools with evidence of steatorrhea; flatulence; abdominal distention; and weight loss. Diagnosis usually can be established by examination of stool or duodenal fluid for cysts or trophozoites. Quinacrine hydrochloride is the drug preferred for treatment, but metronidazole and furazolidone are also useful.

Secretory IgA in protein-calorie malnutrition.

The secretory IgA system was investigated in children with protein-calorie malnutrition (PCM). The results of the study indicated that in children suffering from kwashiorkor and marasmus the concentration of IgA in duodenal fluid, saliva, nasal secretions, and tears was significantly reduced on admission and returned to normal 4 weeks after treatment. However, the concentration of secretory IgA in children with mild to moderate PCM was similar to that of normal children. Secretory IgA deficiency may be an important factor in promoting bacterial growth and this may account for the increased incidence and severity of mucosal infections in children with severe PCM.

Secretory and Serum IgA in Children With Protein-Calorie Malnutrition

The local immune system of children suffering protein-calorie malnutrition (PCM) was investigated by analyzing the amount of immunoglobulins in the nasal washing on admission, repeatedly during 84 days of hospital therapy, and on follow-up, one to two years later. Although measured concentrations of total protein, IgG, and albumin in nasal washings were reduced in children with PCM, only secretory IgA concentrations were significantly lower (P less than .01) in PCM compared to normal children. Mean secretory IgA concentrations were significantly reduced on admission through hospital day 70 and returned to near normal thereafter. At one to two years after hospital discharge, mean concentrations of secretory IgA in nasal secretions were within normal limits. The concentrations of secretory IgA in nasal washings were lowest at a time when serum IgA was markedly elevated; serum IgA concentrations fell to normal values during dietary treatment. The possible role of secretory IgA deficiency in PCM and infection is discussed.