Magda Carneiro-Sampaio

IgG Placental Transfer in Healthy and Pathological Pregnancies

Placental transfer of maternal IgG antibodies to the fetus is an important mechanism that provides protection to the infant while his/her humoral response is inefficient. IgG is the only antibody class that significantly crosses the human placenta. This crossing is mediated by FcRn expressed on syncytiotrophoblast cells. There is evidence that IgG transfer depends on the following: (i) maternal levels of total IgG and specific antibodies, (ii) gestational age, (iii) placental integrity, (iv) IgG subclass, and (v) nature of antigen, being more intense for thymus-dependent ones. These features represent the basis for maternal immunization strategies aimed at protecting newborns against neonatal and infantile infectious diseases. In some situations, such as mothers with primary immunodeficiencies, exogenous IgG acquired by intravenous immunoglobulin therapy crosses the placenta in similar patterns to endogenous immunoglobulins and may also protect the offspring from infections in early life. Inversely, harmful autoantibodies may cross the placenta and cause transitory autoimmune disease in the neonate.

Primary Immunodeficiency Diseases in Latin America: The Second Report of the LAGID Registry

This is the second report on the continuing efforts of LAGID to increase the recognition and registration of patients with primary immunodeficiency diseases in 12 Latin American countries: Argentina, Brazil, Chile, Colombia, Costa Rica, Honduras, Mexico, Panama, Paraguay, Peru, Uruguay, and Venezuela. This report reveals that from a total of 3321 patients registered, the most common form of primary immunodeficiency disease was predominantly antibody deficiency (53.2%) with IgA deficiency reported as the most frequent phenotype. This category was followed by 22.6% other well-defined ID syndromes, 9.5% combined T- and B-cell inmunodeficiency, 8.6% phagocytic disorders, 3.3% diseases of immune dysregulation, and 2.8% complement deficiencies. All countries that participated in the first publication in 1998 reported an increase in registered primary immunodeficiency cases, ranging between 10 and 80%. A comparison of the estimated minimal incidence of X-linked agammaglobulinemia, chronic granulomatous disease, and severe combined immunodeficiency between the first report and the present one shows an increase in the reporting of these diseases in all countries. In this report, the estimated minimal incidence of chronic granulomatous disease was between 0.72 and 1.26 cases per 100,000 births in Argentina, Chile, Costa Rica, and Uruguay and the incidence of severe combined immunodeficiency was 1.28 and 3.79 per 100,000 births in Chile and Costa Rica, respectively. However, these diseases are underreported in other participating countries. In addition to a better diagnosis of primary immunodeficiency diseases, more work on improving the registration of patients by each participating country and by countries that have not yet joined LAGID is still needed.

Autoimmunity in IgA deficiency: revisiting the role of IgA as a silent housekeeper.

Both systemic and organ-specific autoimmune diseases are major manifestations of IgA deficiency (IgAD), the most common primary immunodeficiency. In addition, to discuss the clinical findings of IgAD patients, we proposed a hypothesis to explain the high association with autoimmune phenomena. Based on observations, interactions of monomeric IgA with FcαRI result in a partial phosphorylation of FcRγ-associated FcαRI, notably in the immunoreceptor tyrosine-based activation motif (ITAM) inducing the recruitment of the SHP-1 tyrosine phosphatase. This leads to deactivation of several activating pathways of the immune system including immunoreceptors that bear ITAM motif and ITAM-independent receptors. Consequently, inflammatory reactions and auto-immune process would be prevented.

Colostral neutrophils express Fcα receptors (CD89) lacking γ chain association and mediate noninflammatory properties of secretory IgA

Colostrum plays an important role in protecting newborn infants against acute gastrointestinal and respiratory infections. IgA antibodies have been considered the major effector component; however, the role of their receptors on colostral phagocytes, especially neutrophils, has not been studied. Here, we demonstrate that CD15+ colostrum neutrophils express IgA Fc receptors (FcαR, CD89) at levels similar to those of blood neutrophils. Most colostral cells (70%) bear secretory IgA (SIgA) on their surface (and intracellularly), whereas blood cells do not. The FcαR on colostral neutrophils was identified as the a.1 isoform with a similar molecular mass (55–75 kDa) as that identified for blood neutrophils. Removal of N‐linked carbohydrates revealed a major protein core of 32 kDa for both cell types. In contrast, co‐immunoprecipitation and immunoblot experiments using a mild detergent, digitonin, revealed a lack of γ chain association with FcαR (γ‐less) exclusively on colostral neutrophils. The functional role of these γ‐less FcαR cells was evaluated by measuring superoxide release and killing of SIgA‐coated enteropathogenic E. coli. No increase in superoxide release was observed in colostral cells compared with blood neutrophils, whereas optimal release was obtained with PMA stimulation. Furthermore, despite similar bacterial phagocytosis index between both cell types, IgA‐mediated bacterial‐killing was not detectable with colostral neutrophils, whereas killing was detectable on blood cells. These results reveal exclusive expression of γ‐less FcαR on colostral neutrophils associated with receptor hyperoccupation by IgA and with low, bacterial‐killing activity, which suggest that this receptor may mediate noninflammatory effects of SIgA.

The spectrum of autoantibodies in IPEX syndrome is broad and includes anti-mitochondrial autoantibodies

IPEX syndrome is a congenital disorder of immune regulation caused by mutations in the FOXP3 gene, which is required for the suppressive function of naturally arising CD4 + CD25 + regulatory T cells. In this case series we evaluated serum samples from 12 patients with IPEX syndrome for the presence of common autoantibodies associated with a broad range of autoimmune disorders. We note that 75% of patients (9/12) had 1 or more autoantibodies, an incidence far above the cumulative rate observed in the general population. The range of autoantibodies differed between patients and there was no predominant autoantibody or pattern of autoantibodies present in this cohort. Surprisingly, one patient had high-titer anti-mitochondrial antibodies (AMA) typically associated with primary biliary cirrhosis (PBC) although the patient had no signs of cholestasis. PBC is a well-characterized autoimmune disease that occurs primarily in women and includes the serological hallmarks of serum AMA and elevated IgM which were both present in this patient. PBC is virtually absent in children with the exception of one reported child with interleukin 2 receptor α (CD25) deficiency which is associated with an IPEX-like regulatory T cell dysfunction. Based on the present data and the available literature we suggest a direct role for CD4 + CD25 + regulatory T cells in restraining B cell autoantibody production and that defects in regulatory T cells may be crucial to the development of PBC.

Colostral Mononuclear Phagocytes are Able to Kill Enteropathogenic Escherichia coli Opsonized with Colostral IgA

Enteropathogenic Escherichia coli (EPEC) is the main aetiological agent of acute diarrhoea among low socioeconomic level infants in developing countries. Breast‐feeding provides infant protection against acute gastrointestinal and respiratory infections; however, little is known about the protective role of colostral phagocytes in the gut of newborn infants. In the present investigation we studied the ability of human colostral MN phagocytes to kill EPEC as well as the interactions between these cells and colostral and serum opsonins. The authors observed that the microbicidal activity of colostrum MN phagocytes was dependent on previous EPEC opsonization with colostral supernatant or blood serum. A defatted colostrum supernatant pool presented opsonic activity for EPEC killing at levels equivalent to those of normal serum. IgA‐depleted colostrum supernatant showed significantly lower opsonic activity, whereas purified IgA from the same colostrum pool was a potent opsonin which induced EPEC killing at levels equivalent to those of untreated colostrum. Colostral MN phagocytes are able to release superoxide anion when incubated with both EPEC opsonized with untreated colostrum and purified IgA. Purified IgA was also able to restore opsonic activity of IgA‐depleted colostrum. A colostrum pool without C3 and IgG induced EPEC killing by colostral MN phagocytes at rates equivalent to those of untreated colostrum supernatant. Addition of an IgM MoAb (My43) anti‐human Fcα receptor resulted in a significant inhibition of EPEC killing when bacteria were opsonized with purified IgA, suggesting an interaction between IgA and FcαR. With respect to serum opsonins, we observed that IgG plus complement component C3 were necessary to induce EPEC killing by the colostrum MN phagocytes. Colostral phagocyte killing of enteropathogenic bacteria may represent an additional mechanism of breast‐feeding protein against intestinal infections during the first week of life.

Pineal melatonin and the innate immune response: the TNF-α increase after cesarean section suppresses nocturnal melatonin production

Abstract:  The nocturnal surge of melatonin is the endocrine expression of the circadian system and is essential for organizing the timing of various endogenous processes. Previous works suggest that, in the beginning of a defense response, the increase in circulating tumor necrosis factor‐α (TNF‐α) leads to a transient block of nocturnal melatonin production and promotes a disruption of internal time organization. In the present paper, the concentration of melatonin and cytokines [TNF‐α, interferon‐γ (IFN‐γ), interleukin (IL)‐2, IL‐4, IL‐5, IL‐10, IL‐12] in the colostrum (postdelivery day 3) and in the milk (postdelivery days 10, 15, 20 and 30) obtained at midday and midnight from mothers who gave birth by vaginal or cesarean section were compared. The nocturnal melatonin surge observed 3 days after vaginal delivery was absent after cesarean section. IL‐12 presented no daily variation in either case, while daily variations in IFN‐γ, IL‐10, IL‐4 and IL‐5 were observed after vaginal delivery and cesarean section. On the other hand, the increase in TNF‐α after cesarean section resulted in suppression of the nocturnal melatonin surge. Daily variation of IL‐2 was only observed after recovery of the nocturnal melatonin surge, 30 days after cesarean section. The present paper supports the hypothesis of a cross‐talk between the pineal gland and the immune system, which could represent a putative immune–pineal axis.

Primary Immunodeficiency Diseases in Latin America: First Report from Eight Countries Participating in the LAGID

The Latin American Group for Primary Immunodeficiencies, formed in 1993, presently includes 12 countries. One goal was to study the frequency of primary immunodeficiencies in various regions of the American continent and to enhance knowledge about these diseases among primary-care physicians, as well as allergist–immunologists. Important for this purpose was the development of a registry of primary immunodeficiencies using a uniform questionnaire and computerized database. To date, eight countries have collected information on a total of 1428 patients. Predominantly antibody deficiencies were reported in 58% of patients, followed by cellular and antibody immunodeficiencies associated with other abnormalities in 18%, immunodeficiency syndromes associated with granulocyte dysfunction in 8%, phagocytic disorders in 9%, combined cellular and antibody immunodeficiencies in 5%, and complement deficiencies in 2% of patients. The information gathered from this initial analysis of data will serve to expand the patient database to more areas within participating countries and to new countries and to increase collaboration toward better diagnosis and treatment of these diseases.

Injury switches melatonin production source from endocrine (pineal) to paracrine (phagocytes) - melatonin in human colostrum and colostrum phagocytes.

Abstract:  A large number of data show that melatonin has immunomodulatory properties and is produced by immunocompetent cells; also, some evidence suggests a ‘feedback’ of the activated immune system on the pineal gland. In this paper, we studied immune–pineal interactions in colostrum obtained from healthy puerperae and mothers with mastitis taking into account that, (a) melatonin levels in milk reflects pineal activity and (b) colostrum quiescent mononuclear and polymorphonuclear phagocytes from healthy mothers in culture are adequate for evaluating the ability of immunocompetent cells to produce melatonin. Here we compared the diurnal and nocturnal melatonin levels in colostrum from healthy puerperae and mothers with mastitis; this is a unique noninvasive model for determining pineal activity in the proinflammatory phase of a defense response. In addition, we determined the ‘in vitro’ production of melatonin by colostrum immunocompetent cells stimulated by enteropathogenic Escherichia coli or zymosan. Suppression of nocturnal melatonin rise in mothers with mastitis was highly correlated with increased tumor necrosis factor‐α (TNF‐α) secretion. This result, interpreted taking into account the presence of the transcription factor nuclear factor kappa B in pineal gland, suggest that the proinflammatory cytokine can inhibit nocturnal pineal melatonin production. On the other hand, stimulated, but not quiescent, immunocompetent cells secreted in the colostrum produced melatonin in vitro. In addition, this production ceases after bacteria killing. These results suggest that during the response to an injury the production of melatonin can be transiently shifted from an endocrine (pineal) to a paracrine (immunocompetent cells) source.

Immunity to Microbes: Lessons from Primary Immunodeficiencies

Primary immunodeficiency diseases (PIDs) represent a large and heterogeneous group of more than 120 different entities, most of which have now been genetically characterized (77). Increased susceptibility to infections is the predominant manifestation of almost all forms of PID, particularly in infants and children, demonstrating the paramount importance of the immune system in defense against infection. It has long been known that the nature of an immune defect is related to the etiology of an infection. Prime examples are recurrent respiratory infections with pyogenic bacteria in patients with antibody deficiencies, opportunistic infections with fungi and viruses in infants with SCID (severe combined immunodeficiency), Neisseria meningitidis infections as a hallmark of defects in late-complement components, recurrent staphylococcal infections in patients with neutrophil disorders, and susceptibility to weakly virulent mycobacterial diseases and to Salmonella in patients with deficiencies of the interleukin-12 (IL-12)/IL-23-gamma interferon (IFN-γ) axis. Studies of PID patients have actually contributed to clarification of the anti-infection roles of several mechanisms and components of the immune response, as PIDs offer unique opportunities to link phenotypes to immunological functions and to ascribe various classes of immunity to defenses against different microbes. Thus, studies of agammaglobulinemic patients were crucial in elucidating the role of antibodies in immunity to extracellular bacteria and enteroviruses, as were studies of children with Kostmanns syndrome (congenital severe neutropenia) and chronic granulomatous disease (CGD) in defining the critical role of neutrophils and studies of SCID patients in showing the relevance of T-cell immunity in resistance to intracellular pathogens. More recently, as clinical phenotypes are being mapped to gene defects, respective pathophysiologies can be better understood, often with the help of murine knockout models. Here we offer an observational approach to host/parasite relationships, based on clinical features of PID patients. After an exhaustive review of the main infectious manifestations of PID patients described in large published series as well as in our own series, we propose a novel classification of PIDs according to the degrees of clinical susceptibility to infectious agents observed with PID patients, attempting to link selective susceptibility to specific mechanisms and to established genetic defects. Evidence for a causal association between a particular infection and a given PID is available in some cases, but in others, only a small number of patients have been studied. The data were organized in tables that classify susceptibility to each infection as high (when it is a major manifestation of disease), intermediate (when it appears in some cases but not as a rule), and low (when it is seldom seen). We believe that organizing available information in this manner may also be helpful for the physician, whose identification of a given infection may help determine a putative immunodeficiency.