Thymic Dysplasia Research Articles

Incontinentia pigmenti underlies thymic dysplasia, autoantibodies to type I IFNs, and viral diseases.

Human inborn errors of thymic T cell tolerance underlie the production of autoantibodies (auto-Abs) neutralizing type I IFNs, which predispose to severe viral diseases. We analyze 131 female patients with X-linked dominant incontinentia pigmenti (IP), heterozygous for loss-of-function (LOF) NEMO variants, from 99 kindreds in 10 countries. Forty-seven of these patients (36%) have auto-Abs neutralizing IFN-α and/or IFN-ω, a proportion 23 times higher than that for age-matched female controls. This proportion remains stable from the age of 6 years onward. On imaging, female patients with IP have a small, abnormally structured thymus. Auto-Abs against type I IFNs confer a predisposition to life-threatening viral diseases. By contrast, patients with IP lacking auto-Abs against type I IFNs are at no particular risk of viral disease. These results suggest that IP accelerates thymic involution, thereby underlying the production of auto-Abs neutralizing type I IFNs in at least a third of female patients with IP, predisposing them to life-threatening viral diseases.

Th1/interferon-γ bias in 22q11.2 deletion syndrome is driven by memory T cells and exacerbated by IL-7

The aim of this study was to investigate the impact of thymic dysplasia on the phenotypic and functional characteristics of T cells in patients with 22q11.2 deletion syndrome, including T-cell phenotype, transcriptional profile, cytokine production, as well as the possibility of utilizing IL-7 to recover their numbers and function.We found a strong bias towards Th1 response in pediatric and young adult 22q11.2DS patients, expansion of CXCR5+ follicular helper cells and CXCR3+CCR6− Th1 cells, increased production of cytokines IFN-γ, IL-10, IL-2, IL-21 and TNF-α. This Th1 skew was primarily driven by expanded terminally differentiated T cells. IL-7 further reduced naive T cells, increased cytokine production and caused an upregulation of exhaustion markers.Thus, Th1 bias in T cell populations persists from infancy into adolescence and is accompanied by accelerated maturation of T cells into memory stages. This phenotype is exacerbated by IL-7 which causes further decrease in naïve T cells in vitro.

Death from human cytomegalovirus infection in a girl with congenital thymic dysplasia

We report the case of a girl with congenital thymic dysplasia and refractory disseminated Human Cytomegalovirus (CMV) infection diagnosed by autopsy. Additionally, she was diagnosed with T-cell lymphopenia immunodeficiency and received antiviral therapy with ganciclovir (GCV) /valganciclovir (V-GCV) and enhanced foscarnet. The CMV viral load (VL) monitoring was elevated with retinitis, interstitial pneumonia, and hepatitis. The phenotype of T-cell lymphopenia was uncertain, which limited any alternative therapy by whole-exome sequencing (WES) and lymphocyte subset panel until autopsy. The girl died of progressive respiratory failure and septic shock at ten months of age. Severe disseminated CMV infection typically develops in infants with primary maternal infections and occurs earlier during gestation and in people with a weakened host immune system. Individuals with CMV infection with initial immunodeficiency are associated with a poor prognosis, which is similar to patients with secondary immunodeficiency. This case describes the difficult treatment and prognosis of CMV infection in patients with congenital immunodeficiency, highlighting the importance of early aggressive anti-CMV antiviral therapy in immunodeficiencies, VL monitoring, drug resistance and the role of T-cells in CMV infection.

Fine-tuning of β-catenin in mouse thymic epithelial cells is required for postnatal T-cell development.

In the thymus, the thymic epithelium provides a microenvironment essential for the development of functionally competent and self-tolerant T cells. Previous findings showed that modulation of Wnt/β-catenin signaling in mouse thymic epithelial cells (TECs) disrupts embryonic thymus organogenesis. However, the role of β-catenin in TECs for postnatal T-cell development remains to be elucidated. Here, we analyzed gain-of-function (GOF) and loss-of-function (LOF) of β-catenin highly specific in mouse TECs. We found that GOF of β-catenin in TECs results in severe thymic dysplasia and T-cell deficiency beginning from the embryonic period. By contrast, LOF of β-catenin in TECs reduces the number of cortical TECs and thymocytes modestly and only postnatally. These results indicate that fine-tuning of β-catenin expression within a permissive range is required for TECs to generate an optimal microenvironment to support postnatal T-cell development.

Anncaliia algerae

Anncaliia algerae belongs to the microsporidia, a group of obligate intracellular pathogens originally classified as early branching 'primitive' protozoa but now understood to be related to the Cryptomycota as a basal branch in the fungal kingdom. A. algerae has emerged as a rare opportunistic human pathogen in immune compromised patients such as those taking immune suppressive medications for arthritis, hematologic malignancy, or organ transplantation. It was originally identified as a pathogen of mosquitoes and is probably transmitted to humans by food or water through ingestion, inhalation, or contamination of ocular tissue or wounds with environmental spores. A. algerae infection primarily causes myositis; however, vocal cord, skin, corneal (in immune competent hosts), and disseminated infections have been reported. Human infection has also been reported with other members of the Anncaliia genus: Anncaliia vesicularum in a HIV patient, and Anncaliia connori in an infant with thymic dysplasia.

Retrospective Analysis of 61 Cases of Children Died of Viral Pneumonia.

Objective To retrospectively analyze the forensic pathological postmortem examination and clinical data of children who died of viral pneumonia in identification of cause of death cases and to discuss the clinical characteristics and pathological features of viral pneumonia in children, in order to provide reference to pathological diagnosis of viral pneumonia in children caused by 2019 novel coronavirus （2019-nCoV） infection. Methods Postmortem examination data from 61 cases of children whose causes of death were identified as viral pneumonia in recent years were collected from the Center of Forensic Identification, Southern Medical University. The gender, age, clinical symptoms and pathological features were comparatively analyzed. Results Among the 61 cases of children who died of viral pneumonia, most were within 2 years old （83.61%）, and a large proportion died within 2 weeks after the onset of the disease （91.80%）. Gross changes in postmortem examination included respiratory mucosal hyperemia, pleural effusion, pulmonary swelling, variegated pulmonary pleura and serosa, as well as focal pulmonary hemorrhage and pulmonary edema. A large proportion of sick children had enlarged mesenteric lymph nodes （83.61%） and thymic dysplasia （21.31%）. Histopathological changes included edema of alveoli and interstitial substance, pneumorrhagia，shedding of alveolar epithelial cells, serous and （or） fibrous exudation in the alveoli, formation of viral inclusions, formation of transparent membranes, infiltration of inflammatory cells that mainly consisted of macrophages and lymphocytes in interstitial substance and alveoli. Viral infections often affected the heart and gastrointestinal tract. Conclusion The clinical symptoms of children with viral pneumonia are difficult to notice, and because the immune systems of children are not fully developed and they have poor immunity, they can easily become severely ill and even die. Analyzing the forensic autopsies and the histopathological characteristics could provide reference for pathological diagnosis of viral pneumonia.

Follicular Helper T Cells in DiGeorge Syndrome.

DiGeorge syndrome is an immunodeficiency characterized by thymic dysplasia resulting in T cell lymphopenia. Most patients suffer from increased susceptibility to infections and heightened prevalence of autoimmune disorders, such as autoimmune thrombocytopenia. B cells in DiGeorge syndrome show impaired maturation, with low switched-memory B cells and a wide spectrum of antibody deficiencies or dysgammaglobulinemia, presumably due to impaired germinal center responses. We set out to evaluate circulating follicular helper T cells (cTFHs) in DiGeorge syndrome, as markers of T–B interaction in the germinal centers in a cohort of 17 patients with partial DiGeorge and 21 healthy controls of similar age. cTFHs were characterized as CXCR5+CD45RA− CD4+ T cells using flow cytometry. We verify previous findings that the population of memory CD4+ T cells is relatively increased in diGeorge patients, corresponding to low naïve T cells and impaired T cell production in the thymus. The population of CXCR5+ memory CD4+ T cells (cTFHs) was significantly expanded in patients with DiGeorge syndrome, but only healthy controls and not DiGeorge syndrome patients showed gradual increase of CXCR5 expression on cTFHs with age. We did not observe correlation between cTFHs and serum IgG levels or population of switched memory B cells. There was no difference in cTFH numbers between DiGeorge patients with/without thrombocytopenia and with/without allergy. Interestingly, we show strong decline of PD1 expression on cTFHs in the first 5 years of life in DiGeorge patients and healthy controls, and gradual increase of PD1 and ICOS expression on CD4− T cells in healthy controls later in life. Thus, here, we show that patients with DiGeorge syndrome have elevated numbers of cTFHs, which, however, do not correlate with autoimmunity, allergy, or production of immunoglobulins. This relative expansion of cTFH cells may be a result of impaired T cell development in patients with thymic dysplasia.

Autoimmunity associated with chemically induced thymic dysplasia.

Autoimmune and inflammatory conditions are frequent complications in patients with reduced numbers of T cells. Here, we describe a mouse model of thymic stromal dysplasia resulting in peripheral T-cell lymphopenia. In Foxn1:CFP-NTR transgenic mice, the bacterial nitroreductase enzyme is expressed in thymic epithelial cells and converts the prodrug CB1954 into a cytotoxic agent. This strategy enables titratable and durable destruction of thymopoietic tissue in early embryogenesis. Our results indicate that the resulting low levels of thymic capacity for T-cell production create a predisposition for the development of a complex autoimmune syndrome, chiefly characterized by inflammatory bowel disease and lymphocytic organ infiltrations. We conclude that the Foxn1:CFP-NTR transgenic mouse strain represents a suitable animal model to optimize established clinical protocols, such as thymus transplantation, to correct various forms of thymic dysplasia and to explore novel treatment options.

Abstract 2814: Effect of kif14 overexpression on tumor formation in mice in a lifespan study

Abstract KIF14 is a mitotic kinesin and microtubule-associated molecular motor that plays an essential role in the last stages of cytokinesis. In multiple cancer types, KIF14, overexpression in tumors correlates with stage, aggressiveness, and poor patient outcomes. There is considerable interest in KIF14 as a possible oncogene, since the KIF14 locus is in a common region of genomic gain in multiple cancers. In this study, wild type BDF-1 mice and a strain constitutively overexpressing Kif14, known as Kif14-Tg mice, were evaluated at the end of their natural lifespan, specifically for the occurrence of tumors. There were approximately fifty mice per genotype, and eighty of these mice have died. These mice were necropsied and the following tissues were collected: kidney, liver, lung, spleen, seminal vesicles, ovary, mammary gland, bone marrow, pituitary gland, eye, and brain. Any gross nodules were also collected. These tissues were then fixed in 10% neutral buffered formalin, processed, sectioned, and stained with hematoxylin and eosin. Although there was no significant difference in mouse weights through the lifespan or in the survival curve between the Kif14-Tg and their wild type littermates, a significant increase in follicular lymphoma and diffuse large B cell lymphoma was seen in Kif14-Tg mice compared to the wild type mice. Thirty-three mice developed either a follicular lymphoma or a diffuse large B cell lymphoma, and twenty-four of those mice were Kif14-Tg mice. These were the two most common tumors in Kif14-Tg mice. Other lesions and tumors that were seen in both strains included thymic lymphoma, sarcomas, myeloid dysplasia, and other carcinomas. Nontumorous lesions were seen in both strains of mice including hydronephrosis and telangiectasia in multiple organs. Ballooning degeneration of the lens of the eyes was observed in five mice from the strain Kif14-Tg. Our finding of increased follicular lymphoma and diffuse large B cell lymphoma proves the first evidence that Kif14 can promote tumor formation in a wild-type background. This is the first evidence that Kif14 may have a role in lymphoma, but complements our earlier finding that Kif14 overexpression can accelerate tumor formation in a mouse model of retinoblastoma. Together, these outcomes further support Kif14’s potential as an oncogene. Citation Format: Natalie Pitt, Kamakshi Sishtla, Mehdi Shadmand, Rania Sulaiman, Anthony L. Sinn, Keith Condon, George E. Sandusky, Timothy W. Corson. Effect of kif14 overexpression on tumor formation in mice in a lifespan study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2814. doi:10.1158/1538-7445.AM2017-2814

Mutation of TNFRSF13B in a child with 22q11 deletion syndrome associated with granulomatous lymphoproliferation

Immunodeficiency, secondary to 22q11.2 deletion syndrome with thymic dysplasia, is variable and does not correlate with other phenotypic features. Rarely, patients exhibit severe T alymphocytosis with severe combined immunodeficiency phenotype,1 but most have mild to moderate lymphocytopenia, with associated partial humoral immunodeficiency, often clinically more severe in early life.

Helios expression in T-regulatory cells in patients with di George Syndrome.

Syndrome diGeorge is associated amongst other clinical signs with various degrees of thymic dysplasia, related immunodeficiency and autoimmune disorders. Helios, a transcription factor from Ikaros family, has been proposed as a marker for thymus derived Tregs. We therefore examined Helios + Tregs in a cohort of patients with genetically proven diGeorge syndrome with typical T cell lymphopenia due to the thymic pathology. T cells, FoxP3+ Tregs and Helios + FoxP3+ Tregs were examined in 52 samples from 37 patients. One patient with diGeorge/CHARGE syndrome with total thymic aplasia was also included. Statistical analysis was performed using a linear regression comparison. Total absolute Tregs were significantly lower in diGeorge patients as compared to controls in all age groups (0-20 years) (p = 0.0016). The difference was more expressed in the first four years of age. Relative Treg numbers expressed as the percentage of Tregs in CD4+ T-cells, however, were not different in patients and controls in all age groups (p = 0.661), neither could we find any significant difference in the percentage of Helios + Tregs between patients and controls (p = 0.238). Helios + Tregs were still present in a patient with diGeorge/CHARGE syndrome with complete athymia 7 years after partially matched unrelated repeated T lymphocytes infusions. Our findings show that while there was a significant decrease in absolute numbers of Tregs in patients with diGeorge syndrome, the relative percentage of this population did not differ between patients and controls. Low absolute Tregs thus reflected typical T cells lymphopenia in patients. Helios expression was not affected in diGeorge syndrome.

Requirements for Physician Competencies in Allergy: Key Clinical Competencies Appropriate for the Care of Patients With Allergic or Immunologic Diseases: A Position Statement of the World Allergy Organization

Allergic diseases are quite prevalent worldwide, and the incidence of allergy is increasing everywhere [1-7]. Because allergic and immunologic processes overlap all organ systems, allergy is not always taught in medical schools as a separate subject. Indeed, lack of recognition of the specialty and of the need to teach about allergic and immunologic diseases results in allergy not being included at all in some medical school curricula [8]. With an estimated 22% of the global population experiencing allergic and immunologic diseases, it is time to recognize and strengthen education in allergy and immunology [8]. The World Allergy Organization (WAO), an alliance of 74 national and regional allergy societies, created this consensus document to establish educational guidelines for worldwide application to help identify and correct allergy education and training deficiencies and to define appropriate competencies. In creating this consensus, it is recognized that each country has its own principles and goals in medical education at the undergraduate and postgraduate levels. This document defines what WAO considers medical practitioners should know to care appropriately for allergic patients.

Umbilical Cord Blood Stem Cell Transplantation in Severe T-Cell Immunodeficiency Disorders

Hematopoietic stem cell transplantation is the treatment of choice for severe primary T-cell immunodeficiencies. When an HLA-identical sibling as the donor is not available, an alternative donor stem cell source is needed. In primary T-cell immunodeficiencies, T-cell–depleted HLA-haploidentical bone marrow transplantation has been particularly successful in reconstituting the immune system in many but not all of the severe T-cell immune deficiency disorders. This study reports the use of umbilical cord blood (UCB) stem cell transplantation in 16 patients with severe T cell immune deficiency disorders. UCB was evaluated as a stem cell source for immune reconstitution in children with severe primary T-cell immunodeficiency disorders, such as severe combined immunodeficiency syndrome (SCID), reticular dysgenesis, thymic dysplasia, combined immunodeficiency disease (CID), and Wiskott-Aldrich syndrome (WAS) when an HLA-matched sibling donor was unavailable. From 1996 through 2004, 16 children diagnosed with se...

Kinetics of T-cell development of umbilical cord blood transplantation in severe T-cell immunodeficiency disorders

Background: Hematopoietic stem-cell transplantation is the treatment of choice for severe primary T-cell immunodeficiencies. When an HLA-identical sibling donor is not available, an alternative donor stem-cell source is needed. In primary T-cell immunodeficiencies, T-cell–depleted HLA-haploidentical bone marrow transplantation has been particularly successful in reconstituting the T-cell immune system in many of the severe combined immunodeficiency syndrome types. However, there are some problems associated with this preparation as a stem donor source, such as increased resistance to engraftment, a long period of time for T-cell engraftment to occur, and failure to engraft B cells and B-cell functions. These problems can be especially troublesome if the patient is infected before the transplantation. Objective: Umbilical cord blood was evaluated as a stem-cell source for immune reconstitution in children with severe primary T-cell immunodeficiency disorders, such as severe combined immunodeficiency syndrome, reticular dysgenesis, thymic dysplasia, and combined immunodeficiency disease, when a matched sibling donor was unavailable. Methods: From January 1996 through July 1997, 6 children received unrelated cord blood stem-cell transplantation after a preparative regimen for the treatment of combined immunodeficiency diseases. The patients ranged in age from 2 weeks to 6 years. The cord blood units were 3 of 6 HLA antigen matches in 2 children, 4 of 6 HLA antigen matches in 3 children, and 5 of 6 HLA antigen matches in 1 child, with molecular HLA-DR mismatch in 3 of the children. Results: The average time for neutrophil engraftment (absolute neutrophil count, >500/mm 3) was 12 days (range, 10 to 15 days), and the average time for platelet engraftment (platelet count, >20,000/mm 3) was 36 days (range, 24 to 50 days). In a patient with reticular dysgenesis, the first transplant failed to engraft but fully engrafted after a second unrelated donor cord blood transplantation. Five of 6 patients exhibited grade I graft-versus-host disease (GvHD), although 1 child experienced grade IV skin and gut GvHD. Immunologic reconstitution demonstrated that cord blood stem-cell transplantation resulted in consistent and stable T-cell, B-cell, and natural killer–cell development. The kinetics of recovery of phenotypic expression and function of T cells occurred between 60 to 100 days and that of natural killer cells at approximately 180 days. B cells engrafted early, and a study of functional B-cell antibody responses revealed that 2 of 2 patients in whom intravenous immune globulin was discontinued have low detectable antibody responses to tetanus and diphtheria toxoid immunizations more than 1 year after the transplantation. Conclusions: Unrelated umbilical donor cord blood is an excellent source of stem cells for transplantation of children with immune deficiency disorders. Benefits include rapid and reliable recovery of immune function, low risk of GvHD, and low viral transmission rate. (J Allergy Clin Immunol 1999;103:823-32.)

Postnatal development of T cells in dogs with X-linked severe combined immunodeficiency.

X-linked severe combined immunodeficiency disease (XSCID) in both humans and dogs results from mutations in the common gamma-chain, gamma c, which is a common component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. Although human and canine XSCID share similar features, such as a failure to thrive, hypogammaglobulinemia, an absent T cell mitogenic response, and thymic dysplasia, near normal percentages of T cells are observed in some affected dogs, whereas XSCID boys have few, if any, circulating T cells. In this study, PBL were analyzed by flow cytometry beginning shortly after birth until 9 wk of age. XSCID dogs < 3 wk of age had an elevated number of B cells and were nearly devoid of T cells, phenotypically resembling most human XSCID patients. At 5 wk of age, however, T cells appeared in approximately one-half of the XSCID dogs, although the absolute number of T cells was one-third of normal in these dogs. While the percentage of CD45RA+ T cells in normal dogs gradually decreased with age from > 90% in neonates to < 40% by 3 to 5 yr of age, in XSCID dogs a rapid decline in the percentage of CD45RA+ T cells was observed, resulting in < 10% CD45RA+ T cells by 7 to 9 wk of age. Maternal engraftment was not detected in any of the XSCID dogs by using a sensitive PCR assay. The appearance of nonmaternally derived T cells in XSCID dogs that undergo a rapid switch from CD45RA+ to CD45RA- suggests that limited thymic emigration and peripheral expansion of T cells can occur in the absence of a functional gamma c.

T cell differentiation/maturation of CD34+ stem cells from HIV-seropositive hemophiliacs in cultured thymic epithelial fragments.

The clinical manifestations of AIDS are predominantly due to the cellular and humoral immune dysfunction caused by HIV infection, and thymic dysplasia caused by HIV infection probably contributes to the T cell lymphopenia. In the present study, T cell differentiation and/or maturation was assessed when enriched CD34+ stem cells (SCs or SC) purified from bone marrow of HIV-seropositive hemophiliacs were cocultured with allogeneic cultured thymic epithelial fragments (CTEFs). When HIV-seropositive hemophiliacs' enriched CD34+ SC were cocultured with allogeneic CTEFs, acquisition of the T cell phenotypic markers CD7, CD2, CD3, CD4, CD8 and T cell receptor for antigen (TCR) alpha beta was observed from cells harvested from the culture media peaking at approximately 28 days. Origin of the differentiated and matured T cells from the CD34+ SC was confirmed by labeling the SC with 5-(and -6)-(((4-chloromethyl)benzoyl)amino)tetra-methyl-rhodamine (CMTMR), a fluorescent cytoplasmic dye, and detecting fluorescence in the differentiated and matured T cell by flow cytometry. In one experiment, CMTMR labeling was omitted and double positive CD4+CD8+ and triple positive CD3+CD4+CD8+ thymocytes were identified. These studies confirmed that thymocyte differentiation/maturation from SC had occurred. In addition, T cells obtained from the CD34+ SC and CTEF cocultures proliferated to phytohemagglutinin stimulation maximally with stem cell donor antigen-presenting cells (APCs) and also proliferated to pooled B cells in a mixed lymphocyte culture (MLC). Furthermore, the T cells produced were tolerant to thymus donor B cell HLA antigens (p < 0.025); though there was slight MLC reactivity to autologous stem cell donor B cell HLA compared to thymic B cells (p < 0.025). These T cells demonstrated positive self-alloreactivity to stem cell HLA antigens in four of nine persons, though decreased compared to pool B cell alloantigens. Furthermore, in three experiments, responsiveness to stem cell donor B cells subsequently disappeared upon further duration of CD34+ SC-CTEF coculture. These studies suggested that CD34+ SC gave rise to accessory cells populating the thymus that contributed to HLA restriction. To further evaluate this hypothesis, two different donors of CD34+ SC were cultured simultaneously with thymic epithelial fragments and MLC reactivity was then examined toward APC of the stem cell donors. In these experiments, T cells responded to stimulation with HLA antigens of the pool B cells and did not respond to thymus donor B cells. In six of eight experiments, the chimeric SC-CTEF T cells did not respond to stimulation with B cells of either stem cell donor. These studies suggest that HLA restriction and tolerance were induced by cells of the stem cell donor as well as the thymic epithelial cell HLA antigens. In summary, these studies demonstrated that HIV-infected hemophiliac bone marrow-derived nonadherent CD34+ SC were capable of differentiating and/or maturing into T cells when cocultured in a normal allogeneic thymic environment. Furthermore, the T cells derived from derived CD34+ SC were capable of differentiating into T cells when cocultured in a normal allogeneic thymic environment, proliferated maximally with APCs from the stem cell donor and were tolerant of thymic HLA class II antigens, and to a lesser degree to stem cell donor B cell HLA antigens.

T lymphocyte development and function in dogs with X-linked severe combined immunodeficiency.

Canine X-linked severe combined immunodeficiency disease (XSCID) is characterized by a failure to thrive, thymic dysplasia, and a lack of a T lymphocyte mitogenic response. As in human XSCID, affected dogs in our colony have a mutation in the IL-2R-gamma gene. This mutation dramatically altered T lymphocyte development, because XSCID thymi were severely reduced in size and cellularity, contained an increased proportion of immature CD4-CD8- thymocytes, a decreased proportion of intermediate CD4+CD8+ thymocytes, and a normal proportion of CD4+CD8- and CD4-CD8+ thymocytes. XSCID thymi were also deficient in the percentage of CD3-L+ thymocytes. Interestingly, several XSCID dogs had normal percentages of CD3-L+ PBL. Although the mutation did not interfere with IL-2 production, PHA-activated XSCID PBL demonstrated severely diminished IL-2 binding and were nonresponsive to IL-2. These results indicate that the lack of a functional IL-2R-gamma chain in dogs with XSCID primarily affects developing CD4-CD8- thymocytes as they acquire the cell surface Ag CD3-L and interferes with the ability of peripheral T lymphocytes to bind and respond to IL-2.

Histologic Characterization of the Thymus in Canine X-Linked Severe Combined Immunodeficiency

This study describes the thymic morphology in 52 dogs (ranging in age from 1 to 79 days) with X-linked severe combined immunodeficiency disease (XSCID). The thymuses from the XSCID dogs and age-matched controls were evaluated histotogically for the presence of Hassall's corpuscles and branchial duct remnants, the degree of corticomedullary differentiation, and lymphoid development and organization. Within this population of XSCID dogs with the same genetic defect, three histologic patterns of thymic dysplasia were recognized. Simple dysplasia, noted in 27 XSCID thymuses, was characterized by varying numbers of lymphocytes, no corticomedullary demarcation, and an absence of Hassall's corpuscles. Dysplasia with Hassall's corpuscles was noted in 21 dogs and consisted of varying numbers of lymphocytes, no corticomedullary demarcation, and varying numbers of Hassall's corpuscles. Dysplasia with partial corticomedullary demarcation, noted in 4 dogs, consisted of relatively normal-looking thymuses with well-defined corticomedullary demarcation and numerous Hassall's corpuscles; however, the lobules were extremely small and the subcapsular cortical region was devoid of lymphocytes. Cystic branchial duct remnants were present in 46 of the 52 XSCID thymuses and were more numerous in those thymuses with the pattern of simple dysplasia. The thymuses of XSCID pups less that 4 weeks of age were of the simple dysplastic type and thymuses of XSCID dogs greater than 4 weeks of age were more developed, as evidenced by increased numbers of Hassall's corpuscles and greater corticomedullary demarcation. In conclusion, the thymic dysplasia and lymphoid hypoplasia associated with X-linked severe combined immunodeficiency disease in the dog does not appear to be due to a developmental arrest but rather due to an active process dependent on factors probably related to the overall genetic defect.

Thymic pathology in primary and secondary immunodeficiencies.

For the sake of clarity and in agreement with the World Health Organization immunodeficiency classification, it is important to distinguish the congenital, inherited malformative lesions called generically 'thymic dysplasia' from the secondary, acquired changes, designated under the broad term of 'severe thymic atrophy'. Thymic dysplasia represents the archetype of thymic changes in cellular immunodeficiency, since there is no example of a thymic dysplasia associated with a normal T-cell function. Thymic dysplasia is observed in several inherited diseases, the most frequent of them being severe combined immunodeficiency. More than the depletion of lymphoid cells, the lack of differentiation of the thymic epithelium, responsible for the absence of Hassal's corpuscles, is the main and constant feature of this condition. Thymic dysplasia underscores the crucial role of the thymic epithelium in the normal differentiation of the T-cell population. Severe thymic atrophy is secondary to various causes, including prolonged protein malnutrition and immunosuppressive or cytotoxic drugs, graft versus host reaction and, chiefly today, chronic viral infection, especially with HIV-1. The morphological changes are similar and are characterized by a partial lymphoid depletion, involving mainly the CD1+ population, necrosis and calcification of epithelial cells, the frequent presence of plasma cells and, more significantly, fibrohyaline changes of the basement membrane of the vessels and thymic epithelium. The severity of the atrophic changes and the immunodeficiency-related manifestations depend on the duration of the aetiological factors and, more significantly, with their early occurrence, within the first months of life. The mechanisms underlying thymic atrophy are poorly understood. A primary impairment of lymphoid cells seems at present to be the most likely hypothesis.

Thymic Involution with Loss of Hassall's Corpuscles Mimicking Thymic Dysplasia in a Child with Transfusion-Associated Graft-Versus-Host Disease

A 7-year-old leukemic girl developed pancytopenia following chemotherapy and was given several transfusions of nonirradiated blood. Within 2 weeks she developed a maculopapular rash, fever, abnormal liver function, diarrhea, and wasting. She became septic and died 6 weeks later. Transfusion-associated graft-versus-host disease (GVHD) was suspected clinically. At autopsy, changes diagnostic of GVHD were present in the skin and liver. The remarkable feature of the case was the histopathology of the thymus, which was morphologically "dysplastic," i.e., minute, lymphoid depleted, devoid of a corticomedullary demarcation, and completely lacking in Hassall's corpuscles. These changes were virtually identical to those seen in the thymus of children with severe combined immunodeficiency disease (SCID). There was no evidence of preexisting immune deficiency. There is compelling experimental evidence that GVHD can produce changes in the thymus that are identical to those of "thymic dysplasia." These observations have led to the hypothesis that immunodeficiency associated with GVHD may stem, in part, from injury to thymic epithelium resulting in defective T cell maturation. As a corollary of this hypothesis, it has been suggested that the pathogenesis of some forms of SCID may involve GVHD-associated injury to the thymus by a maternal allograft acquired in utero. This report further documents thymic pathology in human GVHD and discusses these changes in the light of these ideas.