T. Prescott Atkinson

Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency

Apoptosis is a form of programmed cell death that is controlled by aspartate-specific cysteine proteases called caspases. In the immune system, apoptosis counters the proliferation of lymphocytes to achieve a homeostatic balance, which allows potent responses to pathogens but avoids autoimmunity. The CD95 (Fas, Apo-1) receptor triggers lymphocyte apoptosis by recruiting Fas-associated death domain (FADD), caspase-8 and caspase-10 proteins into a death-inducing signalling complex. Heterozygous mutations in CD95, CD95 ligand or caspase-10 underlie most cases of autoimmune lymphoproliferative syndrome (ALPS), a human disorder that is characterized by defective lymphocyte apoptosis, lymphadenopathy, splenomegaly and autoimmunity. Mutations in caspase-8 have not been described in ALPS, and homozygous caspase-8 deficiency causes embryonic lethality in mice. Here we describe a human kindred with an inherited genetic deficiency of caspase-8. Homozygous individuals manifest defective lymphocyte apoptosis and homeostasis but, unlike individuals affected with ALPS, also have defects in their activation of T lymphocytes, B lymphocytes and natural killer cells, which leads to immunodeficiency. Thus, caspase-8 deficiency in humans is compatible with normal development and shows that caspase-8 has a postnatal role in immune activation of naive lymphocytes.

Aerobic Exercise Attenuates Airway Inflammatory Responses in a Mouse Model of Atopic Asthma

Recent reports indicate that aerobic exercise improves the overall physical fitness and health of asthmatic patients. The specific exercise-induced improvements in the pathology of asthma and the mechanisms by which these improvements occur, however, are ill-defined; thus, the therapeutic potential of exercise in the treatment of asthma remains unappreciated. Using an OVA-driven mouse model, we examined the role of aerobic exercise in modulating inflammatory responses associated with atopic asthma. Data demonstrate that moderate intensity aerobic exercise training decreased leukocyte infiltration, cytokine production, adhesion molecule expression, and structural remodeling within the lungs of OVA-sensitized mice (n = 6–10; p < 0.05). Because the transcription factor NF-κB regulates the expression of a variety of genes that encode inflammatory mediators, we monitored changes in NF-κB activation in the lungs of exercised/sensitized mice. Results show that exercise decreased NF-κB nuclear translocation and IκBα phosphorylation, indicating that exercise decreased NF-κB activation in the lungs of sensitized mice (n = 6). Taken together, these results suggest that aerobic exercise attenuates airway inflammation in a mouse model of atopic asthma via modulation of NF-κB activation. Potential exists, therefore, for the amelioration of asthma-associated chronic airway inflammation through the use of aerobic exercise training as a non-drug therapeutic modality.

Oral and Nasal Sensitization Promote Distinct Immune Responses and Lung Reactivity in a Mouse Model of Peanut Allergy

Despite structural and functional differences between the initial sites of contact with allergens in the gastrointestinal and nasal tracts, few animal models have examined the influence of the mucosal routes of sensitization on host reactivity to food or environmental antigens. We compared the oral and nasal routes of peanut sensitization for the development of a mouse model of allergy. Mice were sensitized by administration of peanut proteins in the presence of cholera toxin as adjuvant. Antibody and cytokine responses were characterized, as well as airway reactivity to nasal challenge with peanut or unrelated antigens. Oral sensitization promoted higher levels of IgE, but lower IgG responses, than nasal sensitization. Both orally and nasally sensitized mice experienced airway hyperreactivity on nasal peanut challenge. The peanut challenge also induced lung eosinophilia and type 2 helper T-cell-type cytokines in orally sensitized mice. In contrast, peanut challenge in nasally sensitized mice promoted neutrophilia and higher levels of lung MAC-1(+) I-A(b low) cells and inflammatory cytokines. In addition, nasal but not oral, sensitization promoted lung inflammatory responses to unrelated antigens. In summary, both oral and nasal peanut sensitization prime mice for airway hyperreactivity, but the initial mucosal route of sensitization influences the nature of lung inflammatory responses to peanut and unrelated allergens.

Identification of an alternatively spliced isoform of the fyn tyrosine kinase

Two isoforms of the src-family tyrosine kinase p59fyn have been shown to arise through alternative splicing of exon 7 of the fyn gene. These isoforms have been designated fynT, expressed in hematopoietic cells, and fynB, expressed in the brain. Here, we describe a novel isoform, fynDelta7, in which exon 7 is absent. FynDelta7 mRNA transcripts have been identified in peripheral blood mononuclear cells from all individuals tested thus far and semi-quantitative RT-PCR indicates that this fyn transcript is expressed at near wild-type levels. Transcripts coding for the fynDelta7 isoform can be detected in purified B cells, T cells, NK cells, and monocytes, indicating that it is not lineage specific. We further show that the message isolated is functional using an in vitro expression system and by its expression in COS cells.

Pulmonary aneurysms and intracardiac thrombi due to Behçet’s disease in an African-American adolescent with oculocutaneous albinism

Behçet’s disease (BD) is a systemic vasculitis that may involve a variety of organs. We describe a girl with oculocutaneous albinism (OCA) who, on initial evaluation for popliteal artery occlusion, was noted to have multiple cardiac thrombi. She later developed hemoptysis, which was the result of bilateral pulmonary artery aneurysms. Her clinical picture was consistent with BD. She was initially treated with prednisone and cyclophosphamide, followed by maintenance therapy with infliximab. This case describes a unique patient with OCA who developed BD with large pulmonary aneurysms and has remained stable for over 1xa0year while receiving infliximab.

Leukocyte transfusion-associated granulocyte responses in a patient with X-linked hyper-IgM syndrome

X-linked hyper-IgM syndrome (XHIM) is a severe congenital immunodeficiency caused by mutations in CD154 (CD40 ligand, gp39), the T cell ligand for CD40 on B cells. Chronic or cyclic neutropenia is a frequent complicating feature that heightens susceptibility to severe infections. We describe a patient with a variant of XHIM who produced elevated levels of serum IgA as well as IgM and suffered from chronic severe neutropenia. Eight of ten leukocyte transfusions with cells from a maternal aunt, performed because of mucosal infections, resulted in similar episodes of endogenous granulocyte production. Transfection studies with the mutant CD154 protein indicate that the protein is expressed at the cell surface and forms an aberrant trimer that does not interact with CD40. The data suggest that allogeneic cells from the patients aunt, probably activated T cells bearing functional CD154, may interact with CD40+ recipient cells to produce maturation of myeloid precursors in the bone marrow.

Chapter 84 – Immune Responses to Mycoplasma

This chapter focuses on the host immune response to mycoplasma respiratory infection. M. pneumoniae is often grouped with Chlamydia pneumoniae and Legionella species as bacterial causes of “atypical” community-acquired respiratory infections. The pathogenicity of M. pneumoniae is dependent on its extracellular attachment and the initiation of host cell membrane injury. M. pneumoniae causes physiologic and cytolytic injury to the host cells in part by the production of hydrogen peroxide. Experimental findings suggest important mechanistic links between the pathogenesis of asthma and M. pneumoniae . In direct connection to human asthma, it was found that chronic asthmatics with evidence of respiratory M. pneumoniae infection by PCR had greater numbers of infiltrating mast cells in bronchial biopsies than asthmatics with negative M.pneumoniae PCR. M. pneumonia infection can result in increased expression of M. pneumoniae - specific IgE—this offers another route that infection by this organism could activate mast cells. Furthermore, the pattern of cytokine expression found in mast cells directly activated by M. pneumoniae has a TH2 bias.

Primary immunodeficiency studies at University of Alabama at Birmingham: continuing the search for genetic causes.

Over the past two decades the genetic bases for virtually all the well-characterized primary immunodeficiency syndromes have been identified. The investigation of rare, poorly differentiated immunodeficiencies is being hampered by a preoccupation of funding agencies with hypothesis-driven proposals that apply poorly in the case of individual patients. Recent studies at our institution in collaboration with groups at NIH have resulted in the identification of two separate kindreds bearing unique mutations in molecules affecting immune function and a chromosomal linkage in a third family. Thus, a potential solution to the funding problem for studies in primary immunodeficiency could lie in the centralization of investigative expertise and support, perhaps within the walls of the National Institutes of Health, as has been done with great success in Europe.