Effects of Wiskott-Aldrich Syndrome Protein Deficiency on IL-10-Producing Regulatory B Cells in Humans and Mice.

The Wiskott-Aldrich syndrome protein (WASp) is an important regulator of the actin cytoskeleton and is required for immune cell function. WASp deficiency causes a marked reduction in major mature peripheral B cell subsets, particularly marginal zone (MZ) B cells. We hypothesized that WASp deficiency may also lead to a reduction of regulatory B cells (known as B10 cells) belonging to a novel subset of B cells. And in consideration of the key role of B10 cells play in maintaining peripheral tolerance, we conjectured that a deficit of these cells could contribute to the autoimmunity in patients with Wiskott-Aldrich syndrome (WAS). The effects of WASp deficiency on B10 cells have been reported by only one group, which used an antigen-induced arthritis model. To add more information, we measured the percentage of B10 cells, regulatory T cells (Tregs) and Th1 cells in WASp knockout (WASp KO) mice. We also measured the percentage of B10 cells in patients with WAS by flow cytometry. Importantly, we used the non-induced autoimmune WASp KO mouse model to investigate the association between B10 cell frequency and the Treg/Th1 balance. We found that the percentage of B10 cells was reduced in both mice (steady state and inflammatory state) and in humans and that the lower B10 population correlated with an imbalance in the Treg/Th1 ratio in old WASp KO mice with autoimmune colitis. These findings suggest that WASp plays a crucial role in B10 cell development and that WASp-deficient B10 cells may contribute to autoimmunity in WAS.

[The principle and practice of vidian neurectomy].

The latest research findings on bidirectional regulation of neuro-immunity through traditional neural circuits shed new light on the theoretical basis of the role of vidian neurectomy (VN). This article aims to provide a comprehensive understanding of VN, including the history of VN, the principle of neuroimmuno-interaction, the applied anatomy of VN as well as the methods of transnasal endoscopic surgery. Additionally, we introduce the concept of the nose-brain axis, which was proposed based on the advancement in the area of neuro-immune interactions.

Polymorphisms of STAT5A gene and their association with milk production traits in Holstein cows.

The STAT5A gene was studied as a candidate gene for five milk production traits (milk yield at 305 days, protein percentage, fat percentage, lactose percentage and dry matter percentage) in Holstein cows. According to the sequence of bovine STAT5A gene, two pairs of primers (P1 and P2) were designed to detect polymorphisms of STAT5A gene in 401 Holstein cows by PCR-RFLP and PCR-SSCP. The results showed that the products amplified by primers P1 and P2 displayed polymorphisms. For P1, three genotypes (AA, AG, and GG) were detected, and the frequency of AA/AG/GG was 0.252/0.486/0.262, respectively. Sequence analysis revealed a single nucleotide substitution A-G at 14217 bp (GenBank NC_007317) of bovine STAT5A gene while compared GG genotype with AA genotype. The differences of the least squares means for the four milk production traits (milk yield at 305 days, fat percentage, lactose percentage and dry matter percentage) between AA, AG and GG were not significant (P > 0.05). Least squares mean of protein percentage for AG or GG was significantly higher than that for AA (P < 0.05); the difference of the least squares mean for protein percentage was not significant between AG and GG (P > 0.05). For P2, three genotypes (CC, CT, and TT) were detected in Holstein cows, and the frequency of CC/CT/TT was 0.751/0.234/0.015, respectively. Sequencing revealed an insertion CCT at 17266 (NC_007317) of bovine STAT5A gene while compared CC genotype with TT genotype. The differences of the least squares means for the three milk production traits (protein percentage, lactose percentage and dry matter percentage) between CC, CT and TT were not significant (P > 0.05). Least squares mean of milk yield at 305 days for TT or CT was significantly higher than that for CC (P < 0.05); the difference of the least squares mean for milk yield at 305 days was not significant between TT and CT (P > 0.05). Least squares mean of fat percentage for CC or CT was significantly higher than that for TT (P < 0.05); the difference of the least squares mean for fat percentage was not significant between CC and CT (P > 0.05). The results preliminarily indicated that allele G of A14217G polymorphic site of STAT5A gene is a potential DNA marker for improving protein percentage in dairy cattle, 17266indelCCT polymorphic site of STAT5A gene is a potential DNA marker for improving milk yield at 305 days and fat percentage in dairy cattle.

Perioperative inflammatory response and protein S-100ß concentrations - relationship with post-operative cognitive dysfunction in elderly patients.

BACKGROUND: One major concern in about one third of elder patients after total hip-replacement surgery is post-operative cognitive dysfunction (POCD). Previous studies have suggested that cognitive impairment is accompanied with changes in serum S-100ß protein (S-100ß) and inflammatory markers. Thus, the aim of the current study was to investigate the value of serum S-100ß and interleukin(IL)-1ß, IL-6, tumour necrosis factor-α (TNF-α), and C-reactive protein (CRP) in reflecting POCD after total hip-replacement surgery. METHODS: Forty-two elderly patients were enrolled, and 37 patients completed the follow-up. Serum S-100ß protein and IL-1ß, IL-6, TNF-α, and CRP were determined pre-operatively, as well as 1 h and 6 h post-operatively. Neuropsychological tests were performed pre-operatively, as well as on day 1, 3, and 7 post-operatively. RESULTS: Seventeen (45.9%, 17/37) patients developed POCD 1 day after surgery, and three (8.1%, 3/37) developed POCD 7 days after surgery. [Correction added after publication 7 February 2012: in the preceding sentence (54.1%, 17/37) was corrected to (45.9%, 17/37)]. Patients with POCD 1 day after surgery had significantly higher serum levels of IL-6 at 6 h (135 ± 32 pg/ml vs. 91 ± 29 pg/ml, P < 0.05) and S-100ß at 1 h (1872 ± 385 pg/ml vs. 1289 ± 143 pg/ml, P < 0.05. No significant post-operative change was detected in levels of TNF-α, IL-1, or CRP. CONCLUSION: The serum levels of pro-inflammatory marker IL-6 and S-100ß protein increased after total hip-replacement in elderly patients, and such increase may serve as predicting parameters for the occurrence of POCD.

[Clinical analysis of 12 cases of laryngeal neuroendocrine carcinoma].

Objective: To investigate the clinical and pathological features, treatments and prognosis of laryngeal neuroendocrine carcinoma (LNEC). Methods: We conducted the retrospective analysis of the clinical data of 12 patients with LNEC admitted to the Department of Otorhinolaryngology Head and Neck Surgery, Second Hospital of Shanxi Medical University from May 2014 to December 2021, including 9 males and 3 females, aged 50-77 years. There were 4 cases of typical carcinoid tumour (highly differentiated), 5 cases of atypical carcinoid tumour (moderately differentiated) and 3 cases of neuroendocrine small cell carcinoma (hypofractionated). The clinical features, diagnosis, treatment and prognosis of LNEC were analysed. Results: The clinical manifestations of LNEC varied according to the tumour type but did not correlate with the pathological types. The supraglottic type was characterized by sore throat, foreign body sensation in the pharynx, coughing, obstructive sensation when eating and choking on water. The treatments were determined according to the pathological types, lesion location and invasion scope. Of 12 patients 4 underwent horizontal partial laryngectomy plus elective lymphatic dissection plus postoperative radiotherapy/chemotherapy, 4 underwent vertical partial laryngectomy (3 of them with cervical lymphatic dissection), 3 underwent supported laryngoscopic plasma laryngectomy for laryngeal cancer, and 1 abandoned for treatment. With the follow-up of 8 -78 months, 5 patients were alive, 1 died from chemotherapy reactions, 3 died from other diseases, 1 died from lung metastasis, 1 died from lung infection and 1 was lost to follow-up. Conclusion: LNEC is clinically rare, the clinical manifestations are less specificity, diagnosis relies on pathological and immunohistochemical examinations, and treatment modalities and prognoses are closely related to the pathological subtypes of LNEC.

Clinical and molecular characteristics of immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome in China.

Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare X-linked recessive disorder causing life-threatening systemic autoimmunity because of immunodysregulation. The FOXP3 gene had been reported as the responsible gene, which was critical for the functions of CD4(+) CD25(+) FOXP3(+) regulatory T cells (Tregs) and maintenance of peripheral immunologic tolerance. So far, no IPEX patients with definite mutations in the FOXP3 gene had been reported in China. In this study, the genotypes and phenotypes were investigated in three IPEX infants from three unrelated Chinese families. Patient 1 (P1) presented with a classical clinical phenotype, whose mutation was a novel frameshift insertion in exon 11, led to the complete abrogation of Tregs. Patient 2 (P2) showed incomplete IPEX phenotype. He carried a missense mutation in exon 11 with slightly increased frequency of Tregs, whereas Patient 3 (P3) presented with a relatively mild classical phenotype and had a previously reported missense mutation in exon 10 with decreased frequency of Tregs. We firstly report three Chinese IPEX patients with definite mutations of FOXP3 gene. Our study indicated the potential correlation between the genotype and the phenotype of IPEX, which was different from the previous reports.

[Intravenous immunoglobulin replacement therapy in 114 cases of congenital agammaglobulinemia].

Objective: To analyze the clinical characteristics of congenital agammaglobulinemia and the efficacy of intravenous immunoglobulin (IVIG) replacement therapy for this disease. Methods: The basic characteristics, clinical manifestations, laboratory examinations, and outcomes of 114 patients with congenital agammaglobulinemia diagnosed in Children's Hospital of Chongqing Medical University from January 1988 to April 2020 were retrospectively analyzed. The efficacy of IVIG in improving the clinical symptoms between regular and irregular treatment groups were compared by χ2 test. To explore the clinical characteristics associated with delayed diagnosis and treatment, the patients were also stratified into following subgroups: non-cough, short-term cough and long-term cough groups, chronic lung disease and non-chronic lung disease groups, and arthritis and non-arthritis groups. The age at onset, age at diagnosis, time consumed for diagnosis, initial time of immunoglobulin replacement, dose of IVIG, IgG trough level between the above groups were compared by t test, F test or non-parametric test. Results: All the 114 patients were male, with the onset age of (22±18) months. The age at diagnosis was (89±54) months, time consumed in diagnosis was (63±46) months, and the initial time of immunoglobulin replacement was (75±45) months. A total of 66 patients had been followed up to April 2020, with a follow-up period of (54±41) months. Among these children, 42 (63.6%) received regular infusion, whose monthly IVIG dose was (538±105) mg/kg and IgG trough level was (5.8±1.5) g/L, whereas 24 patients (36.4%) were treated irregularly. There was no significant difference in the improvement rate of fever, cough, sinusitis, diarrhea, otitis media and arthritis between regular and irregular IVIG replacement groups (all P>0.05). Sixty-one out of the 66 patients (92.4%) had fever before IVIG treatment, whose fever episodes were significantly decreased after IVIG treatment (5 (2,12) vs. 0 (0, 1) per year, Z =-6.436, P<0.01). Sixty patients (90.9%) suffered from wet cough before treatment and 36 (54.5%) after treatment. Initial time of immunoglobulin replacement was significantly delayed in the long-term cough (27 cases) and short-term cough groups (9 cases) compared with non-cough group (18 cases) ((97±51) vs. (64±41) vs. (63±42) months, F=3.554, P=0.035). Twenty-nine patients (43.9%) were diagnosed with chronic lung disease, whose initial time of immunoglobulin replacement (103 (75,144) vs. 46 (26,64) months, Z=-4.330, P<0.01), age at diagnosis (103 (75,142) vs. 47 (31,68) months, Z=-3.486, P<0.01), and time consumed in diagnosis (91 (55,129) vs. 29 (10,41) months, Z =-4.386, P<0.01) were significantly later and longer than those in children without chronic lung disease (37 cases). In addition, thirty-two patients(48.5%) were diagnosed with arthritis, whose initial time of immunoglobulin replacement ((98±51) vs. (58±39) months,t=3.420, P=0.001) and time consumed in diagnosis ((74±49) vs. (44±40) months, t=2.600, P=0.010) were also significantly later and longer than those in children without arthritis (34 cases). Conclusions: After immunoglobulin replacement therapy, the clinical symptoms such as fever, sinusitis, diarrhea, and otitis media can be improved more or less. However, long-term wet cough, chronic lung disease, and arthritis are still prominent clinical problems, which could be controlled by standard immunoglobulin replacement therapy in some patients.

Specific immunotherapy suppresses Th2 responses via modulating TIM1/TIM4 interaction on dendritic cells.

BACKGROUND: Specific immunotherapy (SIT) is the only curable remedy for allergic disorders currently; however, the underlying mechanism is not fully understood yet. This study aimed to elucidate the mechanism of SIT on suppressing TIM4 (T cell immunoglobulin mucin domain molecule 4) expression in dendritic cells (DCs) and modulating the skewed T helper 2 (Th2) responses in patients with airway allergy. METHODS: Twenty patients with allergic rhinitis (AR) were treated with SIT for 3 months. Before and after SIT, the expression of TIM4 in peripheral DC and TIM1 in Th2 cells was examined. The role of Fc gamma receptor (FcgammaR) I and II in modulating the expression of TIM4 in DCs was investigated. RESULTS: The interaction of TIM1/TIM4 played a critical role in sustaining the polarization status of Th2 cells in AR patients. Cross-linking FcgammaRI by antigen/IgG complexes increased the production of TIM4 by dendritic cells via upregulating tumor necrosis factor-alpha in DCs. Exposure to microbial products promoted the expression of FcgammaRI in DCs that further increased the expression of TIM4. Exposure to specific antigens alone upregulated the expression of FcgammaRII in DCs, that suppressed the expression of TIM4. CONCLUSIONS: We conclude that SIT suppresses the skewed Th2 responses via disrupting the interaction of TIM1/TIM4 in antigen-specific Th2 cells.

[A case report of BCL11B mutation induced neurodevelopmental disorder and literature review].

Objective: To analyze the clinical , immunological and genetic features of a child with BCL11B mutation induced neurodevelopmental disorder. Methods: The clinical data and genetic test of a child with BCL11B mutation hospitalized in the Department of Rheumatology and Immunology in Children's Hospital of Chongqing Medical University in December 2018 were extracted and analyzed. The literature was searched with "BCL11B mutation" and "immunodeficiency 49" as key words in Chinese databases and Pubmed until January 2019 was reviewed. Results: A male patient aged 3 years and 11 months with facial dysmorphisms and delayed language and motor development was admitted due to neurodevelopmental retardation over two years. Laboratory tests showed normal human immunoglobulin (IgG 12.90 g/L, IgA 1.02 g/L, IgM 1.15 g/L, IgE 532 000 U/L), Trec (228) and proliferation of T and B cells. The lymphocyte subsets revealeda reduced percentage of B cells (0.108) but normal absolute numbers (0.574×10(-3)/L), and an increased percentage (0.828) as well as absolute numbers (4.415×10(-3)/L) of T cells. A heterozygous BCL11B mutation was detected by sanger sequencing, showing a de novo frameshift mutation c.1887_c.1893delCGGCGGG in exon 4. Two papers were found which were all in English, with total of 14 patients(13 patients with complete information). Thirteen mutations were reposed, including 7 frameshift, 2 nonsense, 2 missense, and 2 chromosomal rearrangements; Thirteen patients had heterozygous mutations. All patients had delayed language and motor development and facial dysplasia which were mainly hypertelorism, thin eyebrows and small palpebral fissures. Some patients had dental anomalies, ametropia and allergy, and a few were combined with immune impairment, but without overt signs of immunodeficiency. Only one patient had multisystem anomalies and profound immune deficiency. Conclusions: BCL11B is essential for development of the nervous and the immune system. In this study, the de novo mutation of BCL11B gene resulted in neurodevelopmental and immunological disorders.

[Endoscopic transpterygoid intervention for lesions of lateral recess of sphenoid sinus in 4 cases(with literature review) ].

Objective: To investigate the anatomy and application of endoscopic transpterygoid intervention in lesions of lateral recess of sphenoid sinus(LRSS). Method: Four hospitalized patients with lesions of LRSS were studied. The clinical presentations included spontaneous cerebrospinal fuild(CSF) leakage in 2 cases, meningoencephaolece complicated CSF leakage in 1 case and chronic invasive fungal sphenoid sinusitis invading the base of the middle fossa in 1 case. Endoscopic transpterygoid intervention and repairment of skull base defects were performed under general anesthesia. Result: he operations were successfu1 in all patients. One patient suffered from postoperative palatal hypesthesia and all the symptoms mentioned above relieved gradually 6 months after operation. No recurrence was found during the follow-up ranging from 6 to 45 months(mean follow-up period,22.75 months).Conclusion: Endoscopic transpterygoid intervention in lesions of LRSS is a minimally invasive and safe surgical approach.

[Effects of endogenous glucocorticoid deprivation on immune response of allergic rhinitis in mice].

Objective: To study the effect of dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis on the pathogenesis of allergic rhinitis (AR) by the mouse model of decreased endogenous glucocorticoid (GC) after adrenalectomy, and further explore the mechanism of neural-endocrine regulation. Methods: According to literatures, adrenalectomized (ADX) mice and AR model were established. Eighty mice were randomly divided into four groups (n=20 per group) including control group, AR group of normal mice (AR group), AR group of bilateral ADX (bilateral ADX/AR group) and AR group of unilateral ADX (unilateral ADX/AR group). In order to assess the model of ADX, adrenal gland tissue was assayed by HE staining and the plasma adrenocorticotropic hormone (ACTH) and cortisol (CORT) concentrations were measured by enzyme-linked immunosorbent assay (ELISA). The behavioral observation, OVA-sIgE assessments and count of eosinophils/mast cells by the HE/Toluidine Blue staining of nasal septum mucosa tissue were performed to evaluate the AR model. The expression of peripheral blood CD4(+) IL4(+) T cells (Th2 cells) and CD4(+) IFN-γ(+) T cells (Th1 cells), splenocytes of CD4(+) CD25(+) Treg cells (Treg cells) were measured by flow cytometry to study the influence of endogenous GC on immunological indexes in different groups of mice. SPSS 16.0 software was used to analyze the data. Results: The concentrations of OVA-sIgE in control group, AR group, bilateral ADX/AR group and unilateral ADX/AR group mice were (28.86±3.62) ng/ml, (76.27±16.47) ng/ml, (48.37±8.89) ng/ml, (49.86±7.19) ng/ml, respectively. There was statistically significant difference between control group and AR group (t=7.09, P<0.05), AR group and bilateral ADX/AR group (t=4.81, P<0.05), AR group and unilateral ADX/AR group (t=5.21, P<0.05). The level of Th2 cells in different four groups were (0.71±0.24)%, (7.03±1.95)%, (2.44±2.06)%, (3.20±1.21)%, respectively. There was statistically significant difference between control group and AR group (t=-2.93, P<0.05), AR group and bilateral ADX/AR group (t=-4.67, P<0.05), AR group and unilateral ADX/AR group (t=-3.61, P<0.05). The expression of Th2 in bilateral ADX/AR group is lower than that in unilateral ADX/AR group without significant difference (t=4.39, P>0.05). Meanwhile, the level of Th1 cells in different four groups was (0.58±0.76)%, (0.57±0.59)%, (0.72±0.34)%, (1.03±0.32)%, respectively, with no significant difference among these groups. The proportion of Treg cells was (11.10±2.18)%, (4.10±1.07)%, (7.15±0.92)%, (4.58±1.05)%, respectively, with significant difference between control and other groups (t value was -7.171, -8.273, -8.360, respectively, all P<0.05). Compared with AR group, Treg cells increased significantly in bilateral ADX/AR group (t=-2.607, P<0.05). In addition, lower expression of eosinophil and mast cell were detected in the local nasal tissue of bilateral ADX/AR group, and mast cell degranulation wasn't be observed. Conclusion: Unilateral or bilateral ADX leads to HPA axis dysfunction and endogenous GC deprivation, possibly regulating the mechanism of AR through Th1/Th2 immune bias and Tregs cell' activity.

[A preliminary study of a modified transnasal endoscopic three step vidian neurectomy].

Objective:The aim of this study is to explore an improved trans-nasal endoscopic surgical approach for vidian neurectomy. Method:Ninety-one patients with nasal hyperreactive disease were collected, including 49 cases of allergic rhinitis and 42 cases of non allergic rhinitis. All sufferers enrolled in the study have treated with medicine, but the symptoms were not effectively controlled. Preoperative CT localization of the vidian canal was performed in each candidate. During the surgery a"Three-step" surgical approach were followed under endoscopic guidance in accordance with the operation procedures. Briefly, such a three-step procedure consists of the following, that is, a transnasal endoscopic sphenoidectomy through sphenoethmoidal recess as step one, with enlargement of the sinus ostium along the junction of the anterior wall and the floor of the sinus until the exposure of the vidian nerve canal toward the lateral wall of the sinus as step two. The last step was further exposure of the vidian nerve going through the canal and electric cautery preventing bleeding from the neurovascular bundle in the canal. Result:All patients were completed successfully with 100% preoperative CT location of the vidian canal in the CT scan and 100% intraoperative accurate exposure of the canal and therefore the cut of the vidian nerve. Conclusion:"Three-step" endoscopic resection of the vidian neurectomy is easy to master and repetitive with less injury.

[Analysis of clinical effect of unilateral vidian neurectomy following endoscopic trans-sphenoethmoidal recess approach for allergic rhinitis treatment].

Objective: To explore the clinical efficacy of unilateral vidian neurectomy following endoscopic trans-sphenoethmoidal recess approach in treating allergic rhinitis.Method: The clinical data of 80 patients with moderate-severe allergic rhinitis who underwent unilateral vidian neurectomy following endoscopic trans-sphenoethmoidal recess approach were reviewed retrospectively. Visual analogue scale(VAS) was used to assess total symptom scores and nasal symptoms including nasal itching, nasal sneezing, rhinorrhea and nasal congestion. The paired T test was used to compare the scores between surgical side and control side. Twenty-four patients with 3 years of follow-up were assessed by analysis of variance with comparison of means between multiple groups. Further comparison between any two means was performed by LSD-t test. Result: A total of 80 patients were followed up for one year, with 51 patients for two years and 24 patients for three years. Among 24 patients, total symptom scores and nasal symptoms (nasal itching, nasal sneezing, rhinorrhea and nasal congestion) at pre-operation, 1 year,2 year and 3 year after operation were compared between surgical side and control side. There was no significant difference by the paired T test(P>0.05),but there was statically significant by analysis of variance(P<0.05) .The analysis of LSD-t test showed significant differences between pre-operative time point and each of the three time points after operation (P<0.05). Conclusion:The unilateral vidian neurectomy following endoscopic trans-sphenoethmoidal recess approach is an safe and effective technique in the management of moderate severe allergic rhinitis,and unilateral surgery could relieve bilateral nasal symptoms.

[Clinical and immunological analysis of patients with activated phosphoinositide 3-kinase δ syndrome resulting from PIK3CD mutation].

Objective: To explore the clinical and immunological features, gene mutations, treatment and prognosis in patients with activated phosphoinositide 3-kinase δ syndrome (APDS) caused by PIK3CD gene heterozygous germline mutation. Method: The data of clinical, immunological phenotype, treatment, and prognosis of 15 patients with APDS, who visited Children's Hospital of Chongqing Medical University, Peking Union Medical College Hospital, and Shenzhen Children's Hospital from June 2014 to November 2016, were collected and analyzed. Result: Of the 15 patients, 11 were males, remaining 4 patients were females. The median age of disease onset was 1 year, and median age at diagnosis was 4 years and 4 months. All patients had the de novo heterozygous germline mutation in PIK3CD (c. 3061G>A, p. E1021K). The common initial symptoms were respiratory infections, including pneumonia (12 cases) , bronchiectasis (5 cases). Other common clinical manifestations were recurrent and chronic diarrhea (11 cases), Epstein-Barr virus (EBV) and/or cytomegalovirus (CMV) viremia (10 cases), hepatosplenomegaly (13 cases), and lymphadenopathy (10 cases). The main immunological features were increased IgM (11 cases), decreased IgG (6 cases), decreased numbers of CD4+ T cell (7 cases) especially naïve CD4+ T cell (9 cases), reduced numbers of B cells (11 cases) particularly naïve B cells (9 cases), increased numbers of transitional B cells (5 cases) and CD8+ terminally differentiated effector memory T cells (5 cases). After 1-29 months follow up, 13 of the 15 cases remain survived, of whom 5 cases received regular intravenous immunoglobulin (IVIG) therapy, with reduced frequency of infections and improved severity of infections; of whom 3 cases received oral rapamycin therapy at the dosage of 1 mg/ (m2·d) and with a decrease in nonneoplastic lymphoproliferation. Conclusion: E1021K is a hotspot for mutation in the PIK3CD gene in patients with APDS. Regular IVIG can improve their quality of life. Targetel treatment with rapamycin could mitigate hepatosplenomegaly.