Hyper IgM (HIGM) syndromes are a group of primary immunodeficiency disorders that were defined by Burtin and Rosen in the early 1960s [6]. X-HIGM is a rare primary immunodeficiency disease. Recently, a large-scale study conducted in the United States showed that the incidence of X-HIGM was approximately 1 per 1 million persons [7]. Only about 20% of patients receiving this diagnosis reach the third decade of life [8]. In the treatment of X-HIGM, hematopoietic stem cell transplantation and immunoglobulin replacement therapy have been widely accepted [2]. Variations in CD40 ligand (CD40L, also known as CD154) gene was most commonly associated with X-HIGM, covering 65%-70% of HIGM cases [9,10]. Therefore, understanding the mechanisms of X-HIGM development and progression may be valuable for improving the diagnosis, treatment, and prognosis of children with this syndrome.
Mechanistically, CD40L protein can bind to tumor necrosis factor receptors and CD40 receptors, participate in antiapoptosis, inflammatory responses, leukocyte attachment, signal transduction, platelet activation, B cell proliferation, and isotype conversion. The pathogenesis of HIGM involves antibody class switching recombination dysfunction, with or without somatic hypermutation defects. B cells normally express IgM in the late developmental stages, and then produce IgG and IgA through class switching recombination and somatic hypermutation mechanisms. Any factors interfering with these processes can cause HIGM [11]. Variations and deletions in the CD40LG gene in X-HIGM result in a defective CD40L protein, which, if expressed on the surface, fails to activate CD40 normally [5].
Due to the young age of onset and lack of immune antibodies, X-HIGM patients are easy to get bacterial infection, which including serve bacterial pneumonia, otitis media, sinusitis and so on, pulmonary inflammation is the most common. It has been reported that CD40LG variants can lead to dysfunction of macrophage activation, resulting in excessive accumulation of surfactants in the alveolar cavity and airways, causing pulmonary alveolar proteinosis, which may be the pathological basis of interstitial pneumonia. Also, deficiency of IgG subtype and category conversion memory B cell may lead to pulmonary fibrosis changes [11,12]. Pneumocystis carinii pneumonia is the most common opportunistic infection, the mechanism of it is not clear [13]. As an endolymphoid organ, liver plays an important role in immune balance, and autoimmune liver disease may be the manifestation of HIGM immune deficiency in the liver. Hepatic injury accounts for 50% of HIGM complications, which is the main cause of death in many cases. With the progress of the disease, it can evolve into sclerosing cholangitis and even cholangiocarcinoma [7]. Migration inhibition test and anti-mitochondrial antibody positive may be risk factors for X-HIGM and primary cholangitis [14]. Studies have shown that in patients with primary biliary cirrhosis, elevated serum IgM is often associated with low expression of CD40LG promoter DNA methylation [15]. Granulocyte deficiency may be associated with autoantibodies and CD40L mutations, which mediated by CD40 signaling pathway in inflammatory microenvironment can also lead to granulocyte deficiency [16]. Granulocyte colony stimulating factor can effectively improve neutrophil deficiency. And, autoimmune diseases can occur in X-HIGM patients, the appearance of autoantibodies IgM, immuno-tolerance of peripheral B cells and development defects of regulatory T cell may be responsible to this [4]. Tumor lesions are also common in X-HIGM patients, such as biliary tract tumors, neuroendocrine tumors and so on [17].
Early severe infection and liver disease are the leading causes of death of X-HIGM patients, which timely anti-infection treatment is necessary, it has been reported that even if Pneumocystis carinii was not found in bronchial lavage fluid, early anti-infection treatment should be taken if the it was suspected [18]. Intravenous immunoglobulin (IVIG) is important to improve complications and reduce mortality [19]. IVIG should be initiated actively in the early stage. The routine dose is 400~600 mg/kg, once every 3 weeks, which can significantly correct humoral immune deficiency. The study found that γ- interferon (IFN-γ) and TNF-α increased after percutaneous injection of recombinant CD40L in patients with immunodeficiency, which further improve the immune function of T cells and is beneficial to the defense of opportunistic infection and tumor immune surveillance [20]. But in vivo injection CD40L may lead to other cell line dysfunction while correcting the antibody function of B lymphocytes, and its safety needs further research [21]. Hematopoietic stem cell transplantation (HSCT) is the most effective treatment for X-HIGM. The selection of donor and pre-transplant treatment are very important for the transplantation and reconstruction of autoimmune function after operation. Human leukocyte antigen (HLA) matched sibling is the best donor of hematopoietic stem cells. However, there is a lack of sibling donors in clinic, and most of patients have to receive non-homologous donor transplantation [22]. Also, with the development of technology, gene therapy in X chain of severe diseases combined with immunodeficiency disease and adenosine deaminase deficiency has greatly promoted thetreatment process of X-HIGM. Hubbard successfully edited CD40LG genes in T cells by combining nuclease-induced double-strand breaks with donor carrying recombinant adeno-associated virus, which completly recover CD40L patient's function [23].
In the present study, we identified seven rare nonsynonymous SNVs and three genes with rare nonsynonymous SNVs (CD40LG, BTK, and WAS) associated with immunocompromised disease development in a pedigree with a member diagnosed as having X-HIGM. In this case, the R203 site plays critical roles in the interaction with the CD40 receptor on the B-cell surface, which forms at least three hydrogen bonds (Fig. 5). By contrast, the CD40LR203I variant fails to form hydrogen bond networks with the receptor, which is predicted to deactivate the downstream signaling pathways of B-cell development and antibody class switching (Fig. 6). High-throughput sequencing technologies can detect genetic variations in humans at a single site or numerous sites and have been widely used to study clinical molecular diagnoses. Whole-exome sequencing can quickly identify disease-causing genes and variant sites, and has clear advantages in the detection of monogenic diseases [24]. This way of disease diagnosis is very helpful for early diagnosis, genetic intervention and suitable therapeutic schemes of the disease in the future and further improve the survival rate of the patients and facilitate the development of genetic counselling and prenatal diagnosis.