Research

Acute neonatal infections 'lock-in' a suboptimal CD8+ T cell repertoire with impaired recall responses.

January 28, 2015 By Manish Butte

Acute neonatal infections ‘lock-in’ a suboptimal CD8+ T cell repertoire with impaired recall responses.

PLoS Pathog. 2013 Sep;9(9):e1003572

Authors: Rudd BD, Venturi V, Smith NL, Nzingha K, Goldberg EL, Li G, Nikolich-Zugich J, Davenport MP

Abstract
Microbial infection during various stages of human development produces widely different clinical outcomes, yet the links between age-related changes in the immune compartment and functional immunity remain unclear. The ability of the immune system to respond to specific antigens and mediate protection in early life is closely correlated with the level of diversification of lymphocyte antigen receptors. We have previously shown that the neonatal primary CD8+ T cell response to replication competent virus is significantly constricted compared to the adult response. In the present study, we have analyzed the subsequent formation of neonatal memory CD8+ T cells and their response to secondary infectious challenge. In particular, we asked whether the less diverse CD8+ T cell clonotypes that are elicited by neonatal vaccination with replication competent virus are ‘locked-in’ to the adult memory T cell, and thus may compromise the strength of adult immunity. Here we report that neonatal memory CD8+ T cells mediate poor recall responses compared to adults and are comprised of a repertoire of lower avidity T cells. During a later infectious challenge the neonatal memory CD8+ T cells compete poorly with the fully diverse repertoire of naïve adult CD8+ T cells and are outgrown by the adult primary response. This has important implications for the timing of vaccination in early life.

PMID: 24068921 [PubMed – indexed for MEDLINE]

[A case of autoimmune lymphoproliferactive syndrome and literature review.]

January 27, 2015 By Manish Butte

[A case of autoimmune lymphoproliferactive syndrome and literature review.]

Zhonghua Er Ke Za Zhi. 2014 Dec;52(12):923-926

Authors: Liu L, Hu J, Ma J, Li X, Li F, Li C

Abstract
OBJECTIVE: To summarize the clinical characteristics, diagnosis and treatment of a case with autoimmune lymphoproliferative syndrome (ALPS) .
METHOD: The patient was diagnosed as autoimmune lymphoproliferactive syndrome (ALPS) after being admitted to the Department of Rheumatism and Immunology of Tianjin Children’s Hospital in February 20, 2014. The clinical characteristics, physical examination, laboratory tests, gene tests, and treatment process were analyzed and related literature was reviewed.
RESULT: The patient was a 16-month- old boy.Since the first month of life, he started to have repeatedly fever, diarrhea, shortness of breath, lymphadenopathy, hepatosplenomegaly, anemia (HGBmin 50 g/L) and thrombocytopenia (min 35×10(9)/L) . But multiple exams showed a normal peripheral blood leukocyte count, hypergammaglobulinemia (IgG 19 800 mg/L, IgA 1 710 mg/L, IgM 2 590 mg/L) and significantly increased serum vitamin B12. Flow cytometric measures showed that CD3(+) CD4(-)CD8(-) T lymphocytes significantly increased ( > 10%) at four times. The count of CD3(+)TCRαβ(+)CD4(-)CD8(-)T lymphocytes (double negative T cells; DNTs) >3% twice. The genetic test showed that 309th FAS gene area showed heterozygous mutations, the boy was diagnosed as ALPS. Added examinations of lymphocytes apoptosis induced by FAS was positive. He was treated with prednisone 15 mg once daily and immunomodulator 150 mg three times a day, while in maintaining period with normal levels of hemoglobin and platelet, the dose of prednisone was reduced gradually. Till now, the patient has been treated and observed for 8 months. We retrieved the reports of ALPS in the databases at home and abroad published in recent 10 years, more than 400 cases reported from foreign countries, but there were only 5 domestic cases. Among those, 4 had onset in infancy and 1 at 6-years of age. All the cases presented servere lymphadenopathy and hepatosplenomegaly with anemia (4 of them with hemolytic anemia) and thrombocytopenia. Three cases had a history of frequent infection, one of them had glomerulonephritis. All patient with significant high level of serum immunoglobulin ( > 1.5 times upper limit of normal range), in 3 of them serum vitamin B12 was > 1.5 pg/L (the other 2 cases missed the exam). In 5 cases CD3(+)CD4(-)CD8(-)T cells > 10%, and in 2 case DNTs were 8.9% and 15.7% respectively (the other 3 cases missed the exam). Three cases were clearly detected with FAS mutations. All patients were treated with corticosteroid, 2 of them were added with mycophenolate mofetil. The therapy presented effective result in early 1-3 months, but no long-term follow-up reports were available.
CONCLUSION: ALPS is a disorder of disrupted lymphocyte homeostasis caused by defective Fas-mediated apoptosis, and it is one of the primary immunodeficiency diseases. The onset of the disease occurs during infancy mainly. Clinical lymphoid hyperplasia and autoimmune phenomena are outstanding signs, which can be associated with frequent infections and allergies. The level of serum vitamin B12 > 1.5 pg/L and the count of CD3(+) CD4(-)CD8(-)T cell show important significance. Exact diagnosis should depend on detecting DNTs and FAS gene.

PMID: 25619350 [PubMed – as supplied by publisher]

Hemophagocytic lymphohistiocytosis and primary immune deficiency disorders.

January 27, 2015 By Manish Butte

Hemophagocytic lymphohistiocytosis and primary immune deficiency disorders.

Clin Immunol. 2014 Nov;155(1):118-25

Authors: Faitelson Y, Grunebaum E

Abstract
Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled immune activation and is traditionally associated with inherited gene defects or acquired causes. In addition to abnormalities in cytotoxic granules and lysosomes, various primary immune deficiency disorders (PID) have been identified among patients suffering from HLH. Our purpose was twofold: to better characterize and detail the association between PID and HLH. We found that HLH occurs infrequently among patients with PID, particularly those suffering from abnormalities that impair T cell function. The prognosis of patients suffering from PID and HLH is poor, emphasizing the need for rapid clinical and genetic diagnosis of the PID as well as initiation of appropriate management of the HLH, including allogeneic hematopoietic stem cell transplantations. The association of HLH and PID implicates abnormal T cell function as an important factor in HLH development. It also suggests that the partition of HLH into genetic versus acquired forms might be misleading.

PMID: 25241079 [PubMed – indexed for MEDLINE]

[Primary immunodeficiency diseases: challenges and opportunities for Chinese pediatrician.]

January 27, 2015 By Manish Butte

[Primary immunodeficiency diseases: challenges and opportunities for Chinese pediatrician.]

Zhonghua Er Ke Za Zhi. 2014 Dec;52(12):881-884

Authors: Zhao X

PMID: 25619341 [PubMed – as supplied by publisher]

Pulmonary manifestations in adult patients with chronic granulomatous disease.

January 24, 2015 By Manish Butte

Pulmonary manifestations in adult patients with chronic granulomatous disease.

Eur Respir J. 2015 Jan 22;

Authors: Salvator H, Mahlaoui N, Catherinot E, Rivaud E, Pilmis B, Borie R, Crestani B, Tcherakian C, Suarez F, Dunogue B, Gougerot-Pocidalo MA, Hurtado-Nedelec M, Dreyfus JF, Durieu I, Fouyssac F, Hermine O, Lortholary O, Fischer A, Couderc LJ

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by failure of superoxide production in phagocytic cells. The disease is characterised by recurrent infections and inflammatory events, frequently affecting the lungs. Improvement of life expectancy now allows most patients to reach adulthood. We aimed to describe the pattern of pulmonary manifestations occurring during adulthood in CGD patients. This was a retrospective study of the French national cohort of adult patients (⩾16 years old) with CGD. Medical data were obtained for 67 adult patients. Pulmonary manifestations affected two-thirds of adult patients. Their incidence was significantly higher than in childhood (mean annual rate 0.22 versus 0.07, p=0.01). Infectious risk persisted despite anti-infectious prophylaxis. Invasive fungal infections were frequent (0.11 per year per patient) and asymptomatic in 37% of the cases. They often required lung biopsy for diagnosis (10 out of 30). Noninfectious respiratory events concerned 28% of adult patients, frequently associated with a concomitant fungal infection (40%). They were more frequent in patients with the X-linked form of CGD. Immune-modulator therapies were required in most cases (70%). Respiratory manifestations are major complications of CGD in adulthood. Noninfectious pulmonary manifestations are as deleterious as infectious pneumonia. A specific respiratory monitoring is necessary.

PMID: 25614174 [PubMed – as supplied by publisher]

[Common variable immunodeficiency can present as a multisystemic disorder.]

January 24, 2015 By Manish Butte

[Common variable immunodeficiency can present as a multisystemic disorder.]

Ugeskr Laeger. 2015 Jan 26;177(2A)

Authors: Jørgensen RM, Hansen AB, Cannon SV, Peterslund NA

Abstract
Common variable immunodeficiency is the second most common primary immunodeficiency with a prevalence of approx. 1/10.000-50.000. The clinical challenge is early diagnosis and efficient supportive treatment. The purpose of the present article is to focus on the complexity of the disease, including the risk of a long pre-diagnostic period and to focus on the sarcoidosis-like variant and the possible impact of immunoglobulin subclass deficiency.

PMID: 25612949 [PubMed – as supplied by publisher]

Molecular and clinical study on prevalence of feline herpesvirus type 1 and calicivirus in correlation with feline leukemia and immunodeficiency viruses.

January 23, 2015 By Manish Butte

Molecular and clinical study on prevalence of feline herpesvirus type 1 and calicivirus in correlation with feline leukemia and immunodeficiency viruses.

Vet Res Forum. 2014;5(4):255-61

Authors: Najafi H, Madadgar O, Jamshidi S, Ghalyanchi Langeroudi A, Darzi Lemraski M

Abstract
Upper respiratory tract diseases (URTD) are common clinical problem in cats worldwide. Feline calicivirus (FCV) and feline herpesvirus type 1 (FHV-1) are the main primary pathogens. Feline immunodeficiency virus (FIV) and Feline leukemia virus (FeLV) are also among the most common infectious diseases of cats which suppress the immunity. Oropharyngeal and conjunctival swabs and blood samples were taken from 16 cats with clinical signs of URTD and 26 clinically healthy cats. PCR and RT-PCR were used to detect FHV/FIV or FCV/FeLV infections, respectively. Feline calicivirus was detected in all cats with URTD and 87.00% and 93.00% of them were positive for FIV and FeLV, respectively. Feline herpesvirus rate of infection was 43.00% in sick cats. In clinically normal cats, prevalence rates of FCV and FHV were about 50.00%, but FIV and FeLV rates (42.00% and 65.00% respectively) were higher compared to other studies. Stomatitis was observed in 50.00% of cats with URTD. The main causative agent of corneal ulcers is FHV-1, but in 50.00% of cats with corneal ulcers, FCV was detected alone. It seems new variants of Caliciviruses are the main causative agents to attack uncommon tissues like cornea, although retroviral infections may be in the background of these various signs. The high retroviral prevalence may be due to existence of large population of stray cats. This is the first molecular study of FeLV and FCV in Iran and seems that FCV and FHV prevalence rates in FIV or FeLV infected cats is more than other non-infected ones.

PMID: 25610576 [PubMed]

Clinical Characteristics of Adults with Chronic Rhinosinusitis and Specific Antibody Deficiency.

January 23, 2015 By Manish Butte

Clinical Characteristics of Adults with Chronic Rhinosinusitis and Specific Antibody Deficiency.

J Allergy Clin Immunol Pract. 2014 Nov 25;

Authors: Kashani S, Carr TF, Grammer LC, Schleimer RP, Hulse KE, Kato A, Kern RC, Conley DB, Chandra RK, Tan BK, Peters AT

Abstract
BACKGROUND: Specific antibody deficiency (SAD) involves a deficient response to a polysaccharide vaccine in the setting of normal immunoglobulin G (IgG) levels and chronic infections. Patients with chronic rhinosinusitis (CRS) are often evaluated for SAD. There are limited data that describe patients with CRS and SAD.
OBJECTIVE: The objective of this study was to better characterize the role of SAD in CRS.
METHODS: We reviewed electronic records of adults with CRS who were evaluated for immunodeficiency with quantitative Ig levels and pre- and postantibody titers to a pneumococcal polysaccharide vaccine (PPV).
RESULTS: Fourteen pneumococcal serotypes were determined in 239 subjects from 2002 to 2009. Of these subjects, 64 had adequate protective titers of 1.3 μg/mL or higher in 7 or more serotypes of the 14 serotypes checked; 56 (23%) had less than 7 protective titers post-PPV and were diagnosed with SAD; and 119 had an adequate response to the vaccine with 7 or more serotypes being higher than 1.3 μg/mL (>50% response) and were characterized as “responders.” Subjects with SAD received more antibiotic courses relative to responders in the 2 years after immunization (3.19 ± 2.64 vs 2.19 ± 2.24, P < .05). Of 56 subjects with SAD, 10 (17.9%) received Ig replacement therapy. Subjects who received Ig had fewer numbers of protective pneumococcal titers post-PPV and had more pneumonia (40.0%) versus subjects with SAD who did not receive Ig (10.9%).
CONCLUSIONS: Of the 239 patients with CRS with normal IgG levels evaluated for immunodeficiency, 56 (23.4%) had SAD. A majority of patients with SAD may not need Ig replacement; however, a subset of patients with SAD benefit from Ig replacement.

PMID: 25609325 [PubMed – as supplied by publisher]

Clinical and mutational features of Vietnamese children with X-linked agammaglobulinemia.

January 23, 2015 By Manish Butte

Clinical and mutational features of Vietnamese children with X-linked agammaglobulinemia.

BMC Pediatr. 2014;14:129

Authors: Vu QV, Wada T, Le HT, Le HT, Van Nguyen AT, Osamu O, Yachie A, Nguyen SN

Abstract
BACKGROUND: X-linked agammaglobulinemia (XLA) is a primary immune deficiency characterized by recurrent bacterial infections and profoundly depressed serum immunoglobulin levels and circulating mature B cells. It is caused by mutations of the Bruton tyrosine kinase (BTK) gene and is the most common form of inherited antibody deficiency. To our knowledge, this is the first report of XLA from Vietnam.
METHODS: We investigated the BTK gene mutations and clinical features of four unrelated Vietnamese children.
RESULTS: The mean ages at onset and at diagnosis were 2.5 and 8 years, respectively. All patients had a medical history of otitis media, pneumonia, and septicemia at the time of diagnosis. Other infections reported included sinusitis, bronchiectasis, arthritis, skin infections, meningitis, and recurrent diarrhea. We identified one previously reported mutation (c.441G >A) and three novel mutations: two frameshifts (c.1770delG and c.1742 delG), and one nonsense (c.1249A >T).
CONCLUSIONS: The delayed diagnosis may be attributable to insufficient awareness of this rare disease on the background of frequent infections even in the immunocompetent pediatric population in Vietnam. Our results further support the importance of molecular genetic testing in diagnosis of XLA.

PMID: 24885015 [PubMed – indexed for MEDLINE]

Autoimmune manifestations in SCID due to IL7R mutations: Omenn syndrome and cytopenias.

January 23, 2015 By Manish Butte

Autoimmune manifestations in SCID due to IL7R mutations: Omenn syndrome and cytopenias.

Hum Immunol. 2014 Jul;75(7):662-6

Authors: Zago CA, Jacob CM, de Albuquerque Diniz EM, Lovisolo SM, Zerbini MC, Dorna M, Watanabe L, Fernandes JF, Rocha V, Oliveira JB, Carneiro-Sampaio M

Abstract
B+NK+SCID (severe combined immunodeficiency) due to IL7Rα deficiency represents approximately 10% of American SCID cases. To better understand the spectrum of autoimmune disorders associated with IL7Rα deficiency, we describe two unrelated IL7Rα-deficient female SCID infants whose clinical picture was dominated by autoimmune manifestations: one with intrauterine Omenn syndrome (OS) and another with persistent thrombocytopenic purpura since 4months of age. The OS baby harbored a homozygous p.C118Y mutation in IL7R. She presented dense eosinophilic infiltrates in several organs, including pancarditis, which may have contributed to her death (on the 2nd day of life). B cells were observed in lymph nodes, spleen, bone marrow and thymus. The second patient harbored compound heterozygous p.C118Y and p.I121NfsX8 mutations. She underwent a successful unrelated cord blood transplant. In conclusion, early OS can be observed in patients with IL7R mutations, and autoimmune cytopenias could also complicate the clinical course of SCID babies with this type of defect.

PMID: 24759676 [PubMed – indexed for MEDLINE]