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58-517: FHL may refer to: Fachhochschule Lübeck , a German university Familial hemophagocytic lymphohistiocytosis Family History Library , a genealogical research facility in Salt Lake City, Utah, United States Federal Hockey League , an American ice hockey league Federal Hockey League (Canada) , a defunct Canadian ice hockey league Flexor hallucis longus muscle Friday Harbor Laboratories ,

116-401: A intracellular pathogen , the cells degrade foreign proteins via antigen processing . These result in peptide fragments, some of which are presented by MHC Class I to the T cell antigen receptor (TCR) on CD8 T cells. The activation of cytotoxic T cells is dependent on several simultaneous interactions between molecules expressed on the surface of the T cell and molecules on the surface of

174-486: A cell are bound to class I MHC molecules, and brought to the surface of the cell by the class I MHC molecule, where they can be recognized by the T cell. If the TCR is specific for that antigen, it binds to the complex of the class I MHC molecule and the antigen, and the T cell destroys the cell. In order for the TCR to bind to the class I MHC molecule, the former must be accompanied by a glycoprotein called CD8 , which binds to

232-414: A class I-restricted antigen. Mature T cells go through different stages, depending on the number of times they have been in contact with the antigen. In the first place, naïve T-lymphocytes are an initial stage of T cell residing in the thymus which have not yet encountered an antigen with affinity for its TCR. T cells that have been in contact with the antigen at least once but have subsequently returned to

290-432: A decreased number of circulating red blood cells , white blood cells , and platelets . The bone marrow may show hemophagocytosis . The liver function tests are usually elevated. A low level of the protein albumin in the blood is common. The serum C reactive protein , erythrocyte sedimentation rate , and ferritin level are markedly elevated. In children, a ferritin above 10000 μg/L is very sensitive and specific for

348-445: A different antigen. Some receptors bind to tissues in the human body itself, so to prevent the body from attacking itself, those self-reactive white blood cells are destroyed during further development in the thymus , in which iodine is necessary for its development and activity. TCRs have two parts, usually an alpha and a beta chain. (Some TCRs have a gamma and a delta chain. They are inherent to act against stress and form part of

406-636: A genetic cause of their disease, but rather HLH will be triggered by infection, malignancy, rheumatic disease, and/or certain treatments (as in the cytokine release syndrome associated with CAR T cell therapy ). Primary HLH is caused by high-penetrance variants in genes associated with the syndrome, and thus is part of the phenotype of several inborn errors of immunity (IEI) . The most common and best studied causes of Primary HLH are loss of function, (i.e. inactivating) mutations in genes that code for proteins cytotoxic T cells and NK cells use to kill targeted cells, such as those infected with pathogens like

464-418: A genetic impairment of granule-mediated cytotoxicity in patients, especially older children and adults, who meet any of the various criteria for HLH. Thus, like shock , one must simultaneously manage both the acute physiologic changes associated with HLH (like systemic inflammation, DIC , hepatitis, etc.) and look deeply for various underlying contributors. The International Histiocyte Society has collected

522-543: A marine biology field station of the University of Washington Topics referred to by the same term [REDACTED] This disambiguation page lists articles associated with the title FHL . If an internal link led you here, you may wish to change the link to point directly to the intended article. Retrieved from " https://en.wikipedia.org/w/index.php?title=FHL&oldid=1053613909 " Category : Disambiguation pages Hidden categories: Short description

580-475: A null mutation at the beta-2 microglobulin (B2M) locus and thus lacking major histocompatibility complex class I molecules and CD8+ T cells, it was found that they did not develop diabetes. CD8 T cells may be necessary to resolve chemotherapy-induced peripheral neuropathy (CIPN). Mice without CD8 T cells show prolonged CIPN compared to normal mice and injection of educated CD8 T cells resolve or prevent CIPN. Cytotoxic T-lymphocytes have been implicated in

638-757: A predominantly proinflammatory effect in the disease. It is also studied that the production of cytokines by the CD8+ cells may accelerate the progresses of the arthritis disease. CD8 T cells have been found to play a role in HIV infection. HIV over time has developed many strategies to evade the host cell immune system. For example, HIV has adopted very high mutation rates to allow them to escape recognition by CD8 T cells. They are also able to down-regulate expression of surface MHC Class I proteins of cells that they infect, in order to further evade destruction by CD8 T cells. If CD8 T cells cannot find, recognize and bind to infected cells,

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696-402: A quiescent or inactive state, are known as memory T cells. This particular stage remains ready to respond again to the specific antigen against which they were stimulated. Finally, when an immune response is triggered, these naive and memory T cells are activated, giving rise to effector T cells that have the capacity to kill pathogens or tumor cells. The threshold for activation of these cells

754-441: A syndrome of intense inflammation it needs to be differentiated from sepsis , which may be extremely challenging. The diagnosis of acquired, or secondary, HLH is usually made in association with infection by viruses, bacteria, fungi, or parasites or in association with lymphoma, autoimmune disease, or metabolic disease. Acquired HLH may have decreased, normal, or increased NK cell activity. A major differential diagnosis of HLH

812-409: A wide functional plasticity after recognising infected or transformed cells, as they are able to produce cytokines (IFN-γ, TNF-α, IL-17) and chemokines (IP-10, lymphotactin), trigger cytolysis of target cells (perforins, granzymes...), and interact with other cells, such as epithelial cells, monocytes, dendritic cells, neutrophils and B cells. In some infections, such as human cytomegalovirus , there

870-491: Is Griscelli syndrome (type 2). This is a rare autosomal recessive disorder characterized by partial albinism, hepatosplenomegaly, pancytopenia, hepatitis, immunologic abnormalities, and lymphohistiocytosis. Most cases have been diagnosed between 4 months and 7 years of age, with a mean age of about 17 months. Three types of Griscelli syndrome are recognised: type 1 has neurologic symptoms and mutations in MYO5A . Prognosis depends on

928-471: Is a T lymphocyte (a type of white blood cell ) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways. Most cytotoxic T cells express T-cell receptors (TCRs) that can recognize a specific antigen . An antigen is a molecule capable of stimulating an immune response and is often produced by cancer cells , viruses, bacteria or intracellular signals. Antigens inside

986-511: Is a clonal expansion of peripheral γδ T cells that have specific TCRs, indicating the adaptive nature of the immune response mediated by these cells. T cells with functionally stable TCRs express both the CD4 and CD8 co-receptors and are therefore termed "double-positive" (DP) T cells (CD4 CD8 ). The double-positive T cells are exposed to a wide variety of self-antigens in the thymus and undergo two selection criteria: Only those T cells that bind to

1044-518: Is a heterogeneous autosomal recessive disorder found to be more prevalent with parental consanguinity. Secondary haemophagocytic lymphohistiocytosis (acquired haemophagocytic lymphohistiocytosis) occurs after strong immunologic activation, such as that which can occur with systemic infection, immunodeficiency, or underlying malignancy. Both forms are characterized by the overwhelming activation of normal T lymphocytes and macrophages, invariably leading to clinical and haematologic alterations and death in

1102-606: Is also used. Methotrexate and vincristine have also been used. Other medications include cytokine targeted therapy . On 20 November 2018, the FDA approved the anti-IFN-gamma monoclonal antibody emapalumab (proprietary name Gamifant) for the treatment of pediatric and adult primary HLH. In October 2021 NHS England published Clinical Commissioning Policy: Anakinra for Haemophagocytic Lymphohistiocytosis (HLH) for adults and children in all ages , allowing Anakinra (a modified recombinant interleukin 1 receptor antagonist ) to be used in

1160-461: Is an autosomal recessive disease, hence each sibling of a child with familial HLH has a twenty-five–percent chance of developing the disease, a fifty-percent chance of carrying the defective gene (which is very rarely associated with any risk of disease), and a twenty-five–percent chance of not being affected and not carrying the gene defect. Patients with HLH, especially when untreated, may need intensive therapy . Therefore, HLH should be included in

1218-438: Is caused by IL-1 , IL-6 and TNF-alpha ; the cytopenia is due to the suppressive effect on hematopoiesis by TNF-alpha and TNF-gamma . TNF-alpha and TNF-gamma may also lead to inhibition of lipoprotein lipase or stimulate triglyceride synthesis . Activated macrophages secrete ferritin and plasminogen activator leading to hyperfibrinolysis . The blood count typically shows decreased numbers of blood cells —including

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1276-539: Is different from Wikidata All article disambiguation pages All disambiguation pages Familial hemophagocytic lymphohistiocytosis HLH as defined by the HLH-04 criteria is a descriptive diagnosis. Its individual components are non-specific. The onset of HLH occurs before the age of one year in approximately 70 percent of cases. Familial HLH should be suspected if siblings are diagnosed with HLH or if symptoms recur when therapy has been stopped. Familial HLH

1334-1153: Is more often referred to as macrophage activation syndrome (MAS) and occurs most frequently in the juvenile onset and adult onset forms of Still's disease and in systemic lupus erythematosus . It occurs rarely in juvenile idiopathic arthritis , juvenile Kawasaki disease , and rheumatoid arthritis . Secondary HLH also occurs rarely in immunodeficiency disorders such as severe combined immunodeficiency , DiGeorge syndrome , Wiskott–Aldrich syndrome , ataxia–telangiectasia , and dyskeratosis congenita ); and infections caused by EBV, cytomegalovirus , HIV/AIDS , bacteria , protozoa , fungi and SARS-CoV-2 . Secondary HLH may also result from iatrogenic causes such as bone marrow or other organ transplantations; chemotherapy; or therapy with immunosuppressing agents. About 33% of all HLH cases, ~75% of Asian HLH cases, and nearly 100% of HLH cases caused by mutations in SH2D1A (see X-linked lymphoproliferative disease type 1 ) are associated with, and thought to be triggered or promoted by, EBV infection. These cases of HLH are classified as belonging to

1392-654: Is strongly linked to major histocompatibility complex (MHC) class II antigens. The only cells in the body that express MHC class II antigens are constitutive antigen-presenting cells . This strongly suggests that rheumatoid arthritis is caused by unidentified arthritogenic antigens. The antigen could be any exogenous antigen, such as viral proteins, or an endogenous protein. Recently, a number of possible endogenous antigens have been identified, for example, human cartilage glycoprotein 39, heavy chain binding protein and citrullinated protein. Activated CD4+ T lymphocytes stimulate monocytes, macrophages and synovial fibroblasts to elaborate

1450-751: Is suggested to play a key role in CD8 T cell function, acting as a regulatory gene in the adaptive immune response. Studies investigating the effect of loss-of-function Eomesodermin found that a decrease in expression of this transcription factor resulted in decreased amount of perforin produced by CD8 T cells. Unlike antibodies , which are effective against both viral and bacterial infections, cytotoxic T cells are mostly effective against viruses. During hepatitis B virus (HBV) infection, cytotoxic T cells kill infected cells and produce antiviral cytokines capable of purging HBV from viable hepatocytes. They also play an important pathogenic role, contributing to nearly all of

1508-421: Is the hallmark of HLH. All genetic defects for familial HLH are related to granule -dependent cytotoxicity. This inability to remove infected and antigen-presenting cells and terminate the immune response leads to uncontrolled proliferation and activation of the immune system with release of excessive cytokines. These cells then infiltrate organs, releasing more cytokines, which gives the clinical picture. The fever

1566-474: Is very high, and the process can occur via two pathways: thymus-independent (by infected APCs ) or thymus-dependent (by CD4+ T cells ). In the thymus-independent pathway, because the APC is infected, it is highly activated and expresses a large number of co-receptors for coactivation. If APCs are not infected, CD4 cells need to be involved: either to activate the APC by co-stimulation (more common) or to directly activate

1624-742: The Epstein-Barr virus (EBV) or the Dengue virus . These mutations include those in the following genes: UNC13D , STX11 , RAB27A , STXBP2 , LYST , PRF1 1, SH2D1A , BIRC4 , ITK , CD27 , and MAGT1 . Secondary HLH (sHLH) is associated with, and thought to be promoted by, malignant and non-malignant diseases that likewise weaken the ability of the immune system to attack EBV-infected cells. Malignant disorders associated with secondary HLH include T-cell lymphoma , B-cell lymphoma , acute lymphocytic leukemia , acute myeloid leukemia , and myelodysplastic syndrome . In rheumatic diseases, this syndrome

1682-768: The HScore , which can be used to estimate an individual's risk of HLH. In adults, soluble IL-2 receptor has been found to be a very sensitive marker for HLH, demonstrating 100% sensitivity for ruling out HLH below a cutoff of 2400 U/mL and optimal cutoff for ruling in at 2515 U/mL (sensitivity, 100%; specificity, 72.5%), with 93% specificity at >10 000 U/mL. The differential diagnosis of HLH includes secondary HLH and macrophage-activation syndrome or other primary immunodeficiencies that present with hemophagocytic lymphohistiocytosis, such as X-linked lymphoproliferative disease . Other conditions that may be confused with this condition include autoimmune lymphoproliferative syndrome . As

1740-480: The antigen-presenting cell (APC). For instance, consider the two signal model for T C cell activation. A simple activation of naive CD8 T cells requires the interaction with professional antigen-presenting cells, mainly with matured dendritic cells . To generate longlasting memory T cells and to allow repetitive stimulation of cytotoxic T cells, dendritic cells have to interact with both, activated CD4 helper T cells and CD8 T cells. During this process,

1798-700: The CD4 helper T cells "license" the dendritic cells to give a potent activating signal to the naive CD8 T cells. This licensing of antigen-presenting cells by the CD4 T helper cells proceeds by signaling between CD154/CD40L on the T helper cell and the CD40 receptor on the antigen-presenting cell during immunological synapse formation. While in most cases activation is dependent on TCR recognition of antigen, alternative pathways for activation have been described. For example, cytotoxic T cells have been shown to become activated when targeted by other CD8 T cells leading to tolerization of

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1856-537: The MHC-self-antigen complexes weakly are positively selected. Those cells that survive positive and negative selection differentiate into single-positive T cells (either CD4 or CD8 ), depending on whether their TCR recognizes an MHC class I-presented antigen (CD8) or an MHC class II -presented antigen (CD4). It is the CD8 T-cells that will mature and go on to become cytotoxic T cells following their activation with

1914-577: The TCR genes helps create millions of different T cells with different TCRs, helping the body's immune system respond to virtually any protein of an invader. The vast majority of T cells express alpha-beta TCRs (αβ T cells), but some T cells in epithelial tissues (like the gut) express gamma-delta TCRs ( gamma delta T cells ), which recognize non-protein antigens. The latter are characterised by their ability to recognise antigens that are not presented. In addition, they can recognise microbial toxic shock proteins and self-cell stress proteins. T γδ cells possess

1972-509: The Tc cell by secreting IL-2 . If activation occurs, the lymphocyte polarizes its granules towards the site of the synapse and releases them, producing a "lethal hit". At this point, it separates from the target cell, and can move on to another, and another. The target cell dies in about 6 hours, usually by apoptosis. Class I MHC is expressed by all host cells, except for non- nucleated ones, such as erythrocytes . When these cells are infected with

2030-477: The ability to make some cytokines , such as TNF-α and IFN-γ , with antitumour and antimicrobial effects. The immune system must recognize millions of potential antigens. There are fewer than 30,000 genes in the human body, so it is impossible to have one gene for every antigen. Instead, the DNA in millions of white blood cells in the bone marrow is shuffled to create cells with unique receptors, each of which can bind to

2088-405: The absence of treatment. A subtype of primary HLH where the inflammation is limited to the central nervous system has been described. The current (2008) diagnostic criteria for HLH are 1. A molecular diagnosis consistent with HLH. These include the identification of pathologic mutations of PRF1, UNC13D, or STX11. OR 2. Fulfillment of five out of the eight criteria below: In addition, in

2146-427: The case of familial HLH, no evidence of malignancy should be apparent. Not all five out of eight criteria are required for diagnosis of HLH in adults, and a high index of suspicion is required for diagnosis as delay results in increased mortality. The diagnostic criteria were developed in pediatric populations and have not been validated for adult HLH patients. Attempts to improve diagnosis of HLH have included use of

2204-455: The class of Epstein–Barr virus–associated lymphoproliferative diseases and termed EBV+ HLH . Five genetic subtypes (FHL1, FHL2, FHL3, FHL4, and FHL5) are described, with an estimated overall prevalence of one in 50,000 and equal gender distribution. Molecular genetic testing for four of the causative genes, PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5), is available on a clinical basis. Symptoms of FHL are usually evident within

2262-495: The constant portion of the class I MHC molecule. Therefore, these T cells are called CD8 T cells . The affinity between CD8 and the MHC molecule keeps the T C cell and the target cell bound closely together during antigen-specific activation. CD8 T cells are recognized as T C cells once they become activated and are generally classified as having a pre-defined cytotoxic role within the immune system. However, CD8 T cells also have

2320-442: The control of chronic HBV infection. Cytotoxic T cells have been implicated in the progression of arthritis . The main involvement of rheumatoid arthritis is its joint involvement. The synovial membrane is characterised by hyperplasia , increased vascularity and infiltration of inflammatory cells; mainly CD4+ T lymphocytes, which are the main organisers of cell-mediated immune responses. In different studies, rheumatoid arthritis

2378-498: The cytokines interleukin-1 , interleukin-6 and tumour necrosis factor alpha (TNFa), and to secrete metalloproteinases. The first three of which are key in driving inflammation in rheumatoid arthritis. These activated lymphocytes also stimulate B cells to produce immunoglobulins, including rheumatoid factor. Their pathogenic role is unknown, but may be due to complement activation through immune complex formation. Moreover, several animal studies suggest that cytotoxic T cells may have

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2436-530: The cytotoxins perforin , granzymes , and granulysin . Through the action of perforin, granzymes enter the cytoplasm of the target cell and their serine protease function triggers the caspase cascade, which is a series of cysteine proteases that eventually lead to apoptosis (programmed cell death). This is called a "lethal hit” and allows to observe a wave-like death of the target cells. Due to high lipid order and negatively charged phosphatidylserine present in their plasma membrane, T C cells are resistant to

2494-456: The development of various diseases and disorders, for example in transplant rejection (cytotoxic T-lymphocytes attack the new organ after detecting it as foreign, due to HLA variation between donor and recipient); in excessive cytokine production in severe SARS-CoV-2 infection (due to an exaggerated lymphocyte response, a large amount of pro-inflammatory cytokines are generated, damaging the subject); inflammatory and degenerative diseases of

2552-450: The diagnosis of HLH, however, the diagnostic utility for ferritin is less for adult HLH patients. The serum fibrinogen level is usually low and the D-dimer level is elevated. The sphingomyelinase is elevated. Bone marrow biopsy shows histiocytosis . Primary HLH, also known as familial haemophagocytic lymphohistiocytosis (FHL) or familial erythrophagocytic lymphohistiocytosis,

2610-580: The differential diagnosis of intensive care unit patients with cytopenia and hyperferritinemia . Patients in the earlier stages of HLH are frequently hospitalized at internal medicine wards. HLH clinically manifests with fever , enlargement of the liver and spleen , enlarged lymph nodes , yellow discoloration of the skin and eyes , and a rash . Laboratory findings may include elevated triglyceride levels, low fibrinogen levels, transaminitis , and elevated ferritin levels (among others). The vast majority of patients who meet these criteria will not have

2668-466: The disposal of unwanted T lymphocytes during their development or to the lytic activity of certain T H cells than it is to the cytolytic activity of T C effector cells. Engagement of Fas with FasL allows for recruitment of the death-induced signaling complex (DISC). The Fas-associated death domain (FADD) translocates with the DISC, allowing recruitment of procaspases 8 and 10. These caspases then activate

2726-651: The effector caspases 3, 6, and 7, leading to cleavage of death substrates such as lamin A , lamin B1, lamin B2, PARP ( poly ADP ribose polymerase ), and DNA-PKcs (DNA-activated protein kinase). The final result is apoptosis of the cell that expressed Fas. CD8 T cells can also show Activation Induced Cell Death or AICD which is mediated by CD3 receptor complex. Recently, a platelet released protein TLT-1 has been shown to induce AICD like cell death in CD8 T cells The transcription factor Eomesodermin

2784-467: The effects of their perforin and granzyme cytotoxins. A second way to induce apoptosis is via cell-surface interaction between the T C and the infected cell. When a T C is activated it starts to express the surface protein FAS ligand (FasL)(Apo1L)(CD95L), which can bind to Fas (Apo1)(CD95) molecules expressed on the target cell. However, this Fas-Fas ligand interaction is thought to be more important to

2842-526: The epithelial barrier ). Hematopoietic stem cells in the bone marrow migrate into the thymus , where they undergo V(D)J recombination of their beta-chain TCR DNA to form a developmental form of the TCR protein, known as pre-TCR. If that rearrangement is successful, the cells then rearrange their alpha-chain TCR DNA to create a functional alpha-beta TCR complex. This highly-variable genetic rearrangement product in

2900-518: The first few months of life and may even develop in utero . However, symptomatic presentation throughout childhood and even into young adulthood has been observed in some cases. The five subtypes of FHL are each associated with a specific gene: Nearly half of the cases of type 2 familial hemophagocytic lymphohistiocytosis are due to bi-allelic PRF1 mutations. The underlying causes, either inherited or acquired, lead to an unchecked immune response when exposed to triggers. Impaired NK-cell cytotoxicity

2958-419: The latter. Once activated, the T C cell undergoes clonal expansion with the help of the cytokine interleukin 2 (IL-2), which is a growth and differentiation factor for T cells. This increases the number of cells specific for the target antigen that can then travel throughout the body in search of antigen-positive somatic cells . When exposed to infected/dysfunctional somatic cells, T C cells release

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3016-495: The liver injury associated with HBV infection. Platelets have been shown to facilitate the accumulation of virus-specific cytotoxic T cells into the infected liver. In some studies with mice, the injection with CXCR5+ CD8+T cells show a significant decrease of HBsAg . Also, an increase of CXCL13 levels facilitated the recruitment of intrahepatic CXCR5+CD8+T cells and, these types of cells produced high levels of HBV-specific interferon (IFN)-γ and IL-21 , which can help to improve

3074-421: The pooled proportion are fever 97.2%, hepatomegaly 70.2%, splenomegaly 78.4%, thrombocytopenia 90.1%, anemia 76.0%, and serum ferritin ≥500 μg/L 97.1%. The case fatality rate is 14.6% among dengue hemophagocytic lymphohistiocytosis patients. Cytotoxic T cell A cytotoxic T cell (also known as T C , cytotoxic T lymphocyte , CTL , T-killer cell , cytolytic T cell , CD8 T-cell or killer T cell )

3132-526: The published consensus management documents for the many contexts in which HLH occurs and they host full-text versions. Most patients who meet HLH criteria will have secondary cases. Treatment for these patients should focus on the underlying contributors. Additionally, treatment of the inflammation of HLH itself is often required. While optimal treatment of HLH is still being debated, current treatment regimes usually involve high dose corticosteroids , etoposide and cyclosporin . Intravenous immunoglobulin

3190-475: The severity of neurologic manifestations. Type 2 has mutations in RAB27A and haemophagocytic syndrome, with abnormal T-cell and macrophage activation. This type has a grave prognosis if untreated. Type 3 has mutations in melanophilin and is characterized by partial albinism. This type does not pose a threat to those so affected. HLH is a description of an immunophysiologic state in time. It can be dangerous to infer

3248-482: The treatment of HLH. The prognosis is guarded with an overall mortality of 50%. Poor prognostic factors included HLH associated with malignancy, with half the patients dying by 1.4 months compared to 22.8 months for non-tumour associated HLH patients. Secondary HLH in some individuals may be self-limited because patients are able to fully recover after having received only supportive medical treatment (i.e., IV immunoglobulin only). However, long-term remission without

3306-424: The use of cytotoxic and immune-suppressive therapies is unlikely in the majority of adults with HLH and in those with involvement of the central nervous system (brain and/or spinal cord). The first case report of HLH was published in 1939 under the term "Histiocytic Medullary Reticulosis". A second report would come out in 1952 that would rename the disorder that same year. A systematic review recently reported

3364-492: The virus will not be destroyed and will continue to grow. Furthermore, CD8 T cells may be involved in Type 1 diabetes . Studies in a diabetic mouse model showed that CD4+ cells are responsible for the massive infiltration of mononuclear leukocytes into pancreatic islets . However, CD8+ cells have been shown to play an effector role, responsible for the ultimate destruction of islet beta cells. However, in studies with NOD mice carrying

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