Successful Anti-TNF-α Treatment in a Girl with LAD-1 Disease and Autoimmune Manifestations

Abstract

Leukocyte adhesion deficiency type 1 (LAD-1) is an autosomal recessive disorder, caused by the absence or reduced expression of the beta-2 integrins on granulocytes, and characterized by the inability of these cells to emigrate from the bloodstream towards the sites of tissue inflammation. A twelve-year-old girl with a diagnosis of LAD-1 syndrome and recurrent skin and mucosal infections since birth, presented with a two week history of fever, abdominal pain, vomiting, weight loss and polyarthralgia. She underwent an exploratory laparotomy with the finding of inflamed terminal ileum and colon and a normal appendix. Colonoscopy and videocapsule endoscopy showed multiple ileal and colonic mucosal ulcerations, which were compatible with inflammatory bowel disease, confirmed on histological examination. Given the lack of response to conventional therapy (prednisone and mesalamine), a monoclonal anti-TNF-α antibody was started at a dosage of 5 mg/kg at weeks 0,2,4,6 and then every 8 weeks. We observed a significant improvement of all clinical and laboratory parameters after the first weeks of therapy. Five months later, we anticipated the drug's administration every 5 weeks because of a precocious recurrence of symptoms. After 30 months of treatment no relapse nor any relevant side effects have been observed, and corticosteroids were withdrawn. Interestingly, our patient presented a small subset of CD18+ T cells, similarly to previously reported LAD-1 patients with mild phenotype, inflammatory bowel disease and CD18+ somatic revertant T cells. To the best of our knowledge, this is the first LAD-1 pediatric patient with inflammatory autoimmune complications who experienced a positive response to anti-TNF-α treatment.

Reversion Mosaicism in Primary Immunodeficiency Diseases

“…The severity of the clinical phenotype is directly associated with the degree of CD18 deficiency (73). To date, five revertant patients harboring CD18-expressing cells have been reported in LAD-1 (74)(75)(76). The first patient had a compound heterozygous mutation and carried a reversion to the normal sequence in one of the diseasecausing mutations only within a small fraction of CD8 + T-cells.…”

“…In these previous patients, susceptibility to infections was not ameliorated, probably because of the lack of reversion in granulocytes. By contrast, as with the three revertant patients with gastrointestinal manifestations, the latest case of LAD-1 in a patient, who was presumably a revertant patient because of the presence of minimal CD18 + fraction in circulating CD8 + T-cells, was also affected with severe colitis, which was endoscopically compatible with Crohn’s disease ( 76 ). The inflammatory response at barrier sites such as the oral mucosa and probably in the skin and gastrointestinal tract in LAD-1 may be caused by infections because of relative tissue neutropenia and by a defect in the phagocytosis of apoptotic neutrophils by tissue macrophages (i.e., efferocytosis), which acts as signal to down-regulate IL-23 and IL-17 responses ( 77 ).…”

Long term outcome of eight patients with type 1 Leukocyte Adhesion Deficiency (LAD-1): Not only infections, but high risk of autoimmune complications

“…the eight patients during their follow-up: they were detected in consecutive samples of three untransplanted patients (P5, P6, P7), but also in other three transplanted patients (P1, P2, P3). In P5, a patient with moderate LAD-1 not treated with HSCT, Crohn-like colitis and juvenile idiopathic arthritis were diagnosed at 12 of age, and successfully treated with the anti-TNF-α antibody infliximab15 . At 16 years of age we observed the appearance of anti-nuclear antibodies (ANA), perinuclear anti-neutrophil cytoplasmic antibodies (pANCA), anti-beta 2 glycoprotein antibodies (B2GPI) and anti-cardiolipin antibodies.…”

Perinatal Inflammation: Could Partial Blocking of Cell Adhesion Molecule Function Be a Solution?

“…Fuller understanding of the molecular basis of this deficiency offers a promising perspective for introduction of genes into the β2 chain of human hematopoietic stem cells, although until now the only report of successful treatment of this type has been in canine and other animal models [ 83 , 84 , 85 ]. Recently, successful treatment in a girl with LAD-1 with anti-tumor necrosis factor-a (TNF-a) was reported [ 86 ].…”