Corticosteroids and peritonsillar abscess formation in infectious mononucleosis

Peritonsillar abscess formation is an uncommon complication of infectious mononucleosis (IM). Early case reports implicated corticosteroids in the development of such abscesses, however, subsequent studies suggested that these drugs do not promote the formation of abscesses at several sites outside the central nervous system. It has recently been demonstrated that zwitterionic polysaccharides, in bacterial capsules, form complexes with CD4(+) T lymphocytes leading to abscess formation. A patient is presented who developed peritonsillar abscess a few days after initiation of corticosteroid therapy for IM; the medical literature was reviewed in respect of this subject. It appears that the occurrence of these abscesses in IM is not strongly linked to corticosteroid treatment. The authors, therefore, recommend that steroids should not be withheld from patients with severe IM on the basis that they may precipitate the development of peritonsillar abscess.

Immunophenotypic shift in a case of mycosis fungoides with vitreous invasion

The case of an 82-year-old man who developed intraocular extension from mycosis fungoides, a cutaneous T-cell lymphoma, is presented. The patient died soon after intra-ocular involvement occurred. Immunohistochemistry of a skin biopsy, taken early in the course of the disease, disclosed a predominance of T cells with a helper/inducer phenotype (CD4). However, an intraocular infiltrate obtained 7 years later contained mostly T cells with a suppressor/cytotoxic phenotype (CD8). The occurrence of ocular invasion, the change in immunophenotype, and the predominant proliferation of CD8 lymphocytes may have been related to the poor outcome in this patient.

Lymphocyte subsets in conjunctival mucosa-associated-lymphoid-tissue after exposure to retinal-S-antigen

Purpose: To evaluate the immune cell subsets in conjunctival mucosa-associated-lymphoid-tissue (C-MALT) following challenge with antigen. Methods: Ten adult female Lewis rats were studied. Five rats received one drop (5 µL) of retinal S-antigen (500 µg/mL in phosphate buffered saline, PBS) instilled into the lower fornix twice daily for 10 consecutive days. Five rats received PBS only and served as controls for the experiment. Two days after the last instillation the animals were sacrificed and the orbital contents prepared for immunohistological staining. A panel of monoclonal antibodies was used: CD5, CD4, CD8, CD25, and CD45RA. The number of positive cells were counted in sections of epibulbar, forniceal, and tarsal conjunctiva. Results: There was a significant increase in the number of CD8 T lymphocytes in the conjunctiva of animals receiving retinal S-antigen when compared to control animals. Conclusion: Conjunctival instillation of retinal S-antigen causes an immune response in the C-MALT with a significant increase in the CD8 T lymphocyte subset in this tissue. This response may be involved in the induction of tolerance to the encountered antigen.

Th1 not Th17 cells drive spontaneous MS-like disease despite a functional regulatory T cell response

Multiple sclerosis is considered a disease of complex autoimmune etiology, yet there remains a lack of consensus as to specific immune effector mechanisms. Recent analyses of experimental autoimmune encephalomyelitis, the common mouse model of multiple sclerosis, have investigated the relative contribution of Th1 and Th17 CD4 T cell subsets to initial autoimmune central nervous system (CNS) damage. However, inherent in these studies are biases influenced by the adjuvant and toxin needed to break self-tolerance. We investigated spontaneous CNS disease in a clinically relevant, humanized, T cell receptor transgenic mouse model. Mice develop spontaneous, ascending paralysis, allowing unbiased characterization of T cell immunity in an HLA-DR15-restricted T cell repertoire. Analysis of naturally progressing disease shows that IFN?(+) cells dominate disease initiation with IL-17(+) cells apparent in affected tissue only once disease is established. Tregs accumulate in the CNS but are ultimately ineffective at halting disease progression. However, ablation of Tregs causes profound acceleration of disease, with uncontrolled infiltration of lymphocytes into the CNS. This synchronous, severe disease allows characterization of the responses that are deregulated in exacerbated disease: the correlation is with increased CNS CD4 and CD8 IFN? responses. Recovery of the ablated Treg population halts ongoing disease progression and Tregs extracted from the central nervous system at peak disease are functionally competent to regulate myelin specific T cell responses. Thus, in a clinically relevant mouse model of MS, initial disease is IFN? driven and the enhanced central nervous system responses unleashed through Treg ablation comprise IFN? cytokine production by CD4 and CD8 cells, but not IL-17 responses.

Anthrax Lethal Factor as an Immune Target in Humans and Transgenic Mice and the Impact of HLA Polymorphism on CD4⁺ T Cell Immunity

Bacillus anthracis produces a binary toxin composed of protective antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). Most studies have concentrated on induction of toxin-specific antibodies as the correlate of protective immunity, in contrast to which understanding of cellular immunity to these toxins and its impact on infection is limited. We characterized CD4+ T cell immunity to LF in a panel of humanized HLA-DR and DQ transgenic mice and in naturally exposed patients. As the variation in antigen presentation governed by HLA polymorphism has a major impact on protective immunity to specific epitopes, we examined relative binding affinities of LF peptides to purified HLA class II molecules, identifying those regions likely to be of broad applicability to human immune studies through their ability to bind multiple alleles. Transgenics differing only in their expression of human HLA class II alleles showed a marked hierarchy of immunity to LF. Immunogenicity in HLA transgenics was primarily restricted to epitopes from domains II and IV of LF and promiscuous, dominant epitopes, common to all HLA types, were identified in domain II. The relevance of this model was further demonstrated by the fact that a number of the immunodominant epitopes identified in mice were recognized by T cells from humans previously infected with cutaneous anthrax and from vaccinated individuals. The ability of the identified epitopes to confer protective immunity was demonstrated by lethal anthrax challenge of HLA transgenic mice immunized with a peptide subunit vaccine comprising the immunodominant epitopes that we identified.

Combined Analysis of Gamma-H2AX/53BP1 Foci and Caspase Activation in Lymphocyte Subsets Detects Recent and More Remote Radiation Exposures

<p>Analysis of gamma-H2AX foci in blood lymphocytes is a promising approach for rapid dose estimation to support patient triage after a radiation accident but has one major drawback: the rapid decline of foci levels post-exposure cause major uncertainties in situations where the exact timing between exposure and blood sampling is unknown. To address this issue, radiation-induced apoptosis (RIA) in lymphocytes was investigated using fluorogenic inhibitors of caspases (FLICA) as an independent biomarker for radiation exposure, which may complement the gamma-H2AX assay. Ex vivo X-irradiated peripheral blood lymphocytes from 17 volunteers showed dose-and time-dependent increases in radiation-induced apoptosis over the first 3 days after exposure, albeit with considerable interindividual variation. Comparison with gamma-H2AX and 53BP1 foci counts suggested an inverse correlation between numbers of residual foci and radiation-induced apoptosis in lymphocytes at 24 h postirradiation (P = 0.007). In T-helper (CD4), T-cytotoxic (CD8) and B-cells (CD19), some significant differences in radiation induced DSBs or apoptosis were observed, however no correlation between foci and apoptosis in lymphocyte subsets was observed at 24 h postirradiation. While gamma-H2AX and 53BP1 foci were rapidly induced and then repaired after exposure, radiation-induced apoptosis did not become apparent until 24 h after exposure. Data from six volunteers with different ex vivo doses and post-exposure times were used to test the capability of the combined assay. Results show that simultaneous analysis of gamma-H2AX and radiation-induced apoptosis may provide a rapid and more accurate triage tool in situations where the delay between exposure and blood sampling is unknown compared to gamma-H2AX alone. This combined approach may improve the accuracy of dose estimations in cases where blood sampling is performed days after the radiation exposure. </p>

Natural cutaneous anthrax infection, but not vaccination, induces a CD4⁺ T cell response involving diverse cytokines

Background<p style="padding: 0px; margin: 0px 0px 1em; border: 0px; outline: 0px; font-size: 11px; font-family: Verdana, Arial, Helvetica, sans-serif; vertical-align: baseline; overflow: visible; clear: both; line-height: 17.6000003814697px;">Whilst there have been a number of insights into the subsets of CD4<sup style="padding: 0px; margin: 0px;">+</sup> T cells induced by pathogenic<em style="padding: 0px; margin: 0px; border: 0px; outline: 0px; font-weight: inherit; font-family: inherit; vertical-align: baseline;">Bacillus anthracis</em> infections in animal models, how these findings relate to responses generated in naturally infected and vaccinated humans has yet to be fully established. We describe the cytokine profile produced in response to T cell stimulation with a previously defined immunodominant antigen of anthrax, lethal factor (LF), domain IV, in cohorts of individuals with a history of cutaneous anthrax, compared with vaccinees receiving the U.K. licenced Anthrax Vaccine Precipitated (AVP) vaccine.</p>Findings<p style="padding: 0px; margin: 0px 0px 1em; border: 0px; outline: 0px; font-size: 11px; font-family: Verdana, Arial, Helvetica, sans-serif; vertical-align: baseline; overflow: visible; clear: both; line-height: 17.6000003814697px;">We found that immunity following natural cutaneous infection was significantly different from that seen after vaccination. AVP vaccination was found to result in a polarized IFNγ CD4+ T cell response, while the individuals exposed to <em style="padding: 0px; margin: 0px; border: 0px; outline: 0px; font-weight: inherit; font-family: inherit; vertical-align: baseline;">B. anthracis</em> by natural infection mounted a broader cytokine response encompassing IFNγ, IL-5, −9, −10, −13, −17, and −22.</p>Conclusions<p style="padding: 0px; margin: 0px 0px 1em; border: 0px; outline: 0px; font-size: 11px; font-family: Verdana, Arial, Helvetica, sans-serif; vertical-align: baseline; overflow: visible; clear: both; line-height: 17.6000003814697px;">Vaccines seeking to incorporate the robust, long-lasting, CD4 T cell immune responses observed in naturally acquired cutaneous anthrax cases may need to elicit a similarly broad spectrum cellular immune response.</p>

Innate immune activation in neovascular Age-related Macular Degeneration

Purpose: To compare white blood cell populations from persons with neovascular age-related macular degeneration (nAMD) with that of age-matched controls.<br/> <br/>Methods: Immunophenotyping for white blood cell populations (including CD14++CD16-, CD14++CD16+ and CD14+CD16++ monocytes, CD4 and CD8 T-lymphocytes, CD56 natural killer cells, CD19 B-lymphocytes and CD16+HLA-DR- neutrophils), chemokine receptor expression analysis (CX3CR1 and CCR2) as well as cell activation analysis (MHC-II, HLA-DR, CD62L, STAT3) was performed using samples of peripheral blood from nAMD patients and age- and gender-matched controls.<br/> <br/>Results: The percentage of CD4+ T cells was significantly reduced while the percentage of CD11b+ cells and CD16+HLA-DR- neutrophils was significantly increased in nAMD patients compared to controls. The percentage of classical (CD14++CD16-), intermediate (CD14++CD16+) and non-classical (CD14+CD16++) monocytes was similar between nAMD patients and controls, however there was a significant increase of CX3CR1 on the intermediate monocyte subset and on CD16+HLA-DR- neutrophils in nAMD compared to controls. HLA-DR was significantly increased in all monocyte subsets in nAMD compared to controls. Activation of Signal Transducer and Activator of Transcription 3 (STAT3) was significantly increased in nAMD patients compared to controls following stimulation with IL6.<br/> <br/>Conclusions: Our results suggest an increased activation of the innate immune system in patients with nAMD. A better understanding of the role of the innate immune system in the pathogenesis of nAMD may help identify novel biomarkers and thus development of improved therapeutic strategies.