Humoral and cellular responses to casein in patients with food protein–induced enterocolitis to cow's milk

Food protein-induced enterocolitis syndrome (FPIES) is a type of food allergy in which children who eat milk, soy, or other foods develop repetitive vomiting and sometimes diarrhea.  This can lead to dehydration, and, in the longer run, failure to thrive.  But unlike more typical food allergies, FPIES isn’t mediated by IgE antibodies.  In fact, what causes FPIES is still a bit of a mystery.  In this month’s issue of JACI, Caubet and colleagues discuss results of their study on the immune responses seen in FPIES due to cow milk (CM-FPIES) (J Allergy Clin Immunol 2017; 139(2): 572-583).

To do this, they looked that the levels of antibodies, cytokines (chemical messengers), cell counts, and tryptase levels in 38 patients with active and resolved CM-FPIES.  Oral food challenges (OFCs) were performed, and the results from positive OFCs were compared to those from negative OFCs.

What they found is that neutrophils could be responsible cells, which were found to be higher in patients with positive oral food challenges.  The high levels of IL-8, a chemoattractant for neutrophils, also supported their conclusion.  Mast cells may also participate, since IL-9 that was also high is produced by mast cells, and baseline tryptase levels were elevated.  But interestingly, tryptase levels didn’t increase with the positive oral food challenge, meaning that mast cells weren’t activated during a challenge.  Regulatory cytokines, such as IL-10 are likely related to the development of oral tolerance in FPIES.  Additionally, levels of antibodies specific to casein, a key component of milk, were low in children with CM-FPIES.    There remain a lot of unanswered questions about FPIES, but this study helps to shine some light on this mysterious type of food allergy.

Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study

The immune system is very complicated, and sometimes, a mutation in a single protein can cause major problems.  One such protein is Phosphoinositide 3-kinase (PI3Kδ), which, may interfere with the body’s ability to fight off disease upon activation.  In this month’s issue of JACI, Coulter and colleagues look at 53 patients with Activated PI3Kδ Syndrome (APDS) (J Allergy Clin Immunol 2017; 139(2): 597-606).

These 53 patients were found worldwide, and the diagnosis was confirmed by genetic sequencing.  They then looked at the laboratory findings, radiographs, and other clinical features to better understand the presentation of APDS. 

All in all, the presentation of APDS was highly variable.  Some were asymptomatic through adulthood while others developed infections early in childhood, leading to death.  Three required a bone marrow transplantation.  The most common infectious complication was recurrent respiratory tract infections.  Much like other antibody deficiency syndromes, there was a high rate of bronchiectasis.  Almost half of patients had difficulty fighting viruses like herpes, EBV, and CMV.  Swollen lymph nodes and hepato-splenomegaly were also very common.

Interestingly, PI3K mutations didn’t just effect the ability to fight infections.  Eighteen also had inflammatory/autoimmune diseases, most commonly autoimmune cytopenias. Seventeen had nodular mucosal lymphoid hyperplasia and seven developed lymphoma.  Since PI3K3D is associated with the central nervous system, there was also noted to be a high rate of neurodevelopmental morbidity, ranging from speech delays to global developmental delay.

This study provides a description of APDS, a newly recognized form of immunodeficiency.  It can present in so many different ways, so physicians should keep an eye out in patients who have recurrent infections, especially those involving the respiratory tract or those due to herpes viruses.  Treatment with hematopoietic stem cell transplant may be curative, and clinical trials for selective PI3Kδ inhibitors are currently underway.

Factors influencing the infant gut microbiome at age 3-6 months: Findings from the ethnically diverse Vitamin D Antenatal Asthma Reduction Trial (VDAART)

In the gut, there are millions of bacteria and other micro-organisms, collectively called the gut microbiome.  Microbes in the gut are known to be important modulators of the developing immune system.   In this month’s issue of JACI, Sordillo and colleagues look at predictors of the gut microbiome in infancy (J Allergy Clin Immunol 2017; 139(2): 482-491).  Microbes present in this early life window may ultimately affect the risk of allergic disease later in childhood. 

They looked at stool samples in over 300 infants born to mothers in the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a trial in which pregnant women took vitamin D to see how it would impact their children’s health.  In the stool, they looked at the bacterial genes to see what bacteria were present.

They found that race, mode of delivery, and formula-feeding are associated with different composition of gut bacteria.  Black race and caesarean section were independent predictors of having lower levels of Bacteroides.  This is important because lower Bacteroides abundance has already been associated with immune changes predisposing to asthma and allergic disease.  In addition, formula feeding was linked to higher levels of Clostridia.  Previous studies have suggested a link between Clostridia and development of atopic dermatitis, wheezing and allergic sensitization.

This study points out that factors with the potential to increase allergic disease risk are also associated with alterations in the infant gut microbiome, but there are still a lot of unanswered questions.  Do these factors (race, mode of delivery, formula feeding) act via changes in the infant gut microbiome to increase allergic disease risk?  Do these changes in the gut microbiome persist through childhood?  Can breastfeeding change the microbiome and reduce the risk of allergic disease?  Finally, can we figure out which species and subspecies are most closely associated with these risks?  Further research is needed, but this study provides a meaningful step towards providing answers.