Vaccine-associated paralytic poliomyelitis and BCG-osis in an immigrant child with severe combined immunodeficiency syndrome - Texas, 2013.

Poliovirus transmission has been eliminated in most of the world through the use of inactivated poliovirus vaccine (IPV) and live, attenuated oral poliovirus vaccine (OPV). In the United States, use of OPV was discontinued by the year 2000 because of the potential for vaccine-associated paralytic polio (VAPP); an average of eight cases were reported each year in the United States during 1980-2000. Polio eradication efforts in other parts of the world continue to rely on OPV to take advantage of transmission of poliovirus vaccine strains to unvaccinated persons in the population, lower cost, and ease of administration. In 2013, an infant aged 7 months who recently immigrated to the United States from India was referred to a hospital in San Antonio, Texas. The infant had fever, an enlarging skin lesion in the deltoid region with axillary lymphadenopathy, decreased activity, and inability to bear weight on the left leg, progressing to paralysis of the left leg over a 6-week period. Recognition of lymphopenia on complete blood count led to immune evaluation, which revealed the presence of severe combined immunodeficiency syndrome (SCIDS), an inherited disorder. A history of OPV and bacille Calmette-Guérin (BCG) vaccination in India led to the diagnoses of VAPP and BCG-osis, which were confirmed microbiologically. This report demonstrates the importance of obtaining a comprehensive clinical history in a child who has recently immigrated to the United States, with recognition that differing vaccine practices in other countries might require additional consideration of potential etiologies.

Maintenance of immune tolerance to a neo-self acetylcholine receptor antigen with aging: implications for late-onset autoimmunity.

Age-related changes in immune regulation are likely to account for the age-associated increase in serum autoantibody levels and in certain autoimmune disorders, such as myasthenia gravis (MG). To demonstrate directly a loss of immune tolerance in older individuals, responses to the acetylcholine receptor, the autoantigen in MG, were assessed in transgenic mice expressing the Torpedo californica acetylcholine receptor (TAChR) alpha-chain as a neo-self Ag. T cells from young transgenic mice had been shown to be tolerant to p146-162, the TAChR alpha-chain peptide that dominated young nontransgenic T cell responses in vitro. The immunodominance of p146-162 was not lost with age; fine specificity was preserved. Moreover, T cell tolerance to p146-162, as well as to other epitopes of the TAChR alpha-chain extracellular domain, was maintained in old transgenic mice. Even multiple TAChR immunizations coupled with the MG-enhancing cytokine, IL-12, did not break tolerance. In addition, T cells exhibiting CD4 upregulation, an early activation marker, were reduced in frequency equivalently in old and young transgenic animals, suggesting that immune regulation in this model was not impacted by aging. Moreover, B cell tolerance was also maintained with age. The persistence of immune tolerance was accompanied by an increase in the proportion of T regulatory cells; it is speculated that this may compensate for deficiencies in central tolerance that occur owing to thymic involution. In summary, our study reveals, for the first time, that some immune tolerance mechanisms do survive aging; this suggests that certain late-onset autoimmune disorders may be induced by a specific insult that disrupts immune homeostasis.

Clinical and Serologic Response to the 23-valent Polysaccharide Pneumococcal Vaccine in Children and Teens with Recurrent Upper Respiratory Tract Infections and Selective Antibody Deficiency.

We report the clinical and serological response of 72 children and adolescents after immunization with the 23-valent polysaccharide pneumococcal vaccine (PPV23). All had been diagnosed with recurrent upper respiratory tract infections and low antipneumococcal immunity. Forty-five (62%) of these patients had received PCV7, the 7-serotype pneumococcal conjugated vaccine (Prevnar7). After immunization with the polysaccharide vaccine, 69 (96%) patients, including 42 of the 45 who had previously been immunized with the conjugate vaccine, had a positive clinical response including 12 patients (17%) whose serological response to the polysaccharide vaccine was inadequate. Clinical and serological response to PPV23 was assessed at approximately 1, 3 and 6 months after immunization. Our study also confirmed that a small group of patients with recurrent upper respiratory tract infections are unable to develop a normal response to pneumococcal and other bacterial polysaccharides despite vaccination with the newer conjugated vaccines. This immunodeficiency has been named selective antibody deficiency with normal immunoglobulins or impaired polysaccharide responsiveness. These patients did well after administration of intravenous IgG.

Immunological memory and late onset autoimmunity.

This review will address a paradox that has long fascinated scientists studying the effects of aging on the immune system. Although it has been clearly documented that B and T lymphocytes lose the ability to respond to antigenic or mitogenic stimulation with age, it has nonetheless been noted that the frequency of autoreactive antibodies is higher in older individuals. Given that the majority of the age-associated defects in immune regulation target the naïve T and B lymphocyte subsets, it has been presumed that this increase in antibodies specific for self antigens was due to changes in the B cell repertoire and/or to differences in the mechanisms responsible for generating immune tolerance in primary responses. However, in this review, we will address an alternative possibility that memory immune responses, first generated when the individual was young, may play a critical role in the appearance of serum autoantibodies by reactivation later in life (recall memory). It has recently been shown, in several different systems, that memory immunity can be maintained over the lifetime of the animal. Thus, memory B cells which are self-reactive may be harbored within an organism as it ages and the potential exists that they become re-activated at a later time, resulting in a vigorous autoreactive recall response. This may occur preferentially in older individuals due to several factors, including deficiencies in immune tolerance with age, progressive age-associated loss of tissue integrity yielding neo-self antigens, and possible re-exposure to an infectious agent which induces an autoimmune memory response through molecular mimicry. Thus, we propose that some of the autoantibodies seen in elderly patients and in older animals may have been produced by memory lymphocytes originally generated against antigens encountered during one's youth, but maintained in a tolerant (non reactive) state until a subsequent triggering event occurs. Possible implications of this model will be discussed.

Recall immune memory: a new tool for generating late onset autoimmune myasthenia gravis.

Most patients with autoimmune myasthenia gravis (MG) produce autoantibodies against their muscle acetylcholine receptors (AChR), causing debilitating muscle weakness. Approximately 60% of MG patients first exhibit myasthenic symptoms after the age of 40. Yet, in the C57BL/6 mouse model of MG, older mice are resistant to induction of myasthenia gravis. To understand the immunological basis for this resistance, the effects of age on the B-cell responses to AChR from Torpedo californica, the inducing antigen, were addressed. As expected, the primary B-cell response was lower in 20-month-old mice than in 2-month-old mice; the isotype profile was not altered by age. When mice were re-immunized, the anti-T-AChR titers increased in both young and old animals, suggesting that a memory response was elicited. Importantly, memory B-cells activated in young animals were largely resistant to the age-associated loss of immune function and the recall memory response was vigorous. Furthermore, the antibodies produced in re-stimulated older mice were functional, as evidenced by the appearance of MG symptoms in some of these animals. Thus, by eliciting a recall memory response, the first examples of late onset MG in mice have been generated. By analogy, late onset MG in humans may be due to re-activation of B-cell responses initiated at a younger age.

A hierarchy of T cell receptor motifs determines responsiveness to the immunodominant epitope in experimental autoimmune myasthenia gravis.

The predominant murine T lymphocyte population responding to Talpha146-162, the immunodominant epitope in EAMG, expresses the TCRBV 6 gene segment. However, cells expressing other TCRBV gene segments also react with this peptide. In order to more precisely characterize the Talpha146-162-specific TCR repertoire, we isolated CD4high cells from peptide-immunized mice. The majority of CD4high cells utilized an acidic TCR beta chain CDR3 motif regardless of TCRBV gene usage. Analysis of T cell clones demonstrated a fourfold higher avidity of Vbeta6+ than non-Vbeta6 cells for Talpha146-162 indicating that a hierarchy of TCR motifs determines T cell responsiveness in EAMG.

Cryptic determinants and promiscuous sequences on human acetylcholine receptor: HLA-dependent dichotomy in T-cell function.

Experimental autoimmune myasthenia gravis can be induced in some strains of mice and rats by immunizing with acetylcholine receptor. Also, epidemiologic studies demonstrate an MHC linkage of myasthenia gravis in the man. In order to obtain direct experimental evidence for the influence of the genes of the MHC complex in the development of myasthenia gravis, we used mice transgenic to individual HLA molecules. We observed an increased susceptibility to the disease in HLA DQ8 transgenic mice compared to HLA DQ6 transgenic mice ( J. Immunol. 160:4169; 1998). These mice lacked endogenous mouse class II molecules. In the present study we mapped the cryptic and dominant sequences on the extra cellular region of human acetylcholine receptor. Although some epitopes (e.g., alpha11-30, alpha141-160, alpha171-190) were common between DQ8 and DQ6 transgenic mice, several others were disparately recognized. We also found a functional dichotomy in T cells from mice differing by one MHC molecule (HLA DQ8 or DQ6) when primed by sequences immunodominant in DQ8 and DQ6 tg mice. Differential disease manifestation in the two different HLA transgenic mice could be explained not only by differential recognition of peptides by these antigen presenting molecules, but also by the difference in the functional profile of T cells generated when primed by promiscuous sequence regions.

TCRBV CDR3 diversity of CD4+ and CD8+ T-lymphocytes in HIV-infected individuals.

TCRBV CDR3 repertoire diversity was analyzed in a cross-sectional study of HIV-infected individuals by CDR3 fingerprinting/spectratyping and single strand conformation polymorphism (SSCP). Most TCRBV families were detected in CD4+ cells of HIV-infected patients with CD4 counts ranging from 35 to 1103. In patients with CD4 counts >500, CD4+ TCRBV CDR3 fingerprinting profiles contained subtle variations with generally gaussian-distributed sizes. Lower CD4 counts coincided with more fragmented TCRBV CDR3 repertoires, containing dominant bands and bands missing from the CDR3 profiles. The CD8+ population of the same patients exhibited skewed CDR3 profiles of the majority of TCR BV families at CD4 counts >500. Irregularity of CD8+ CDR3 size distribution was most profound at low CD4 counts and suggested domination of the CD8+ TCRBV repertoire by a limited number of clones. Skewed patterns of CDR3 diversity probably reflect (oligo)clonal expansion of particular CD4+ and CD8+ cell populations during chronic infection with HIV. In addition, irregular CDR3 profiles of CD4+ and CD8+ at low CD4 counts suggest diminished TCR repertoire diversity, which may contribute to immunodeficiency.

Risk factors influencing antibody responses to Kaposi's sarcoma-associated herpesvirus latent and lytic antigens in patients under antiretroviral therapy.

BACKGROUND: Kaposi's sarcoma-associated herpesvirus (KSHV) seropositivity and lytic antibody titer are predictors for Kaposi's sarcoma. METHODS: We examined demographic, viral, and immunologic factors that influence KSHV latent and lytic antibodies in HIV-infected patients. RESULTS: Detection rate of KSHV latent but not lytic antibodies was lower in patients with CD4 cells/mm3 less than 200 than greater than 200 (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.11-0.61) and CD8 cells/mm3 less than 400 than greater than 400 (OR, 0.26; 95% CI, 0.07-0.67). Overall seropositivity rate was higher in patients with CD4 cells/mm3 less than 200 than greater than 200 (OR, 2.34; 95% CI, 1.37-4.02) and HIV copies/mL greater than 400 than less than 400 (OR, 1.70; 95% CI, 1.09-2.65). Lytic antibody level was inversely correlated with CD4 count (P < 0.001). Lytic seropositivity (OR, 2.47; 95% CI, 1.35-4.50) and antibody level (adjusted difference mean optical density, 0.324; 95% CI, 0.16-0.46) were higher in patients with HIV infection greater than 15 than less than 15 years. Hispanics had higher lytic seropositivity rate (OR, 1.71; 95% CI, 1.07-2.73) and antibody level (adjusted difference mean optical density, 0.111; 95% CI, 0.03-0.18) than non-Hispanics. CONCLUSIONS: Lower CD4 and CD8 counts impair antibody response to KSHV latent antigens. Immune deterioration, long-term HIV infection, and Hispanic status are risk factors for Kaposi's sarcoma predictors.

Immune competency of a hairless mouse strain for improved preclinical studies in genetically engineered mice.

Genetically engineered mouse models (GEMM) of cancer are of increasing value to preclinical therapeutics. Optical imaging is a cost-effective method of assessing deep-seated tumor growth in GEMMs whose tumors can be encoded to express luminescent or fluorescent reporters, although reporter signal attenuation would be improved if animals were fur-free. In this study, we sought to determine whether hereditable furlessness resulting from a hypomorphic mutation in the Hairless gene would or would not also affect immune competence. By assessing humoral and cellular immunity of the SKH1 mouse line bearing the hypomorphic Hairless mutation, we determined that blood counts, immunoglobulin levels, and CD4+ and CD8+ T cells were comparable between SKH1 and the C57Bl/6 strain. On examination of T-cell subsets, statistically significant differences in naïve T cells (1.7 versus 3.4 x 10(5) cells/spleen in SKH1 versus C57Bl/6, P = 0.008) and memory T cells (1.4 versus 0.13 x 10(6) cells/spleen in SKH1 versus C57Bl/6, P = 0.008) were detected. However, the numerical differences did not result in altered T-cell functional response to antigen rechallenge (keyhole limpet hemocyanin) in a lymph node cell in vitro proliferative assay. Furthermore, interbreeding the SKH1 mouse line to a rhabdomyosarcoma GEMM showed preserved antitumor responses of CD56+ natural killer cells and CD163+ macrophages, without any differences in tumor pathology. The fur-free GEMM was also especially amenable to multiplex optical imaging. Thus, SKH1 represents an immune competent, fur-free mouse strain that may be of use for interbreeding to other genetically engineered mouse models of cancer for improved preclinical studies.

Discrete T cell populations with specificity for a neo-self-antigen bear distinct imprints of tolerance.

Mice expressing the Torpedo acetylcholine receptor alpha-chain as a neo-self-Ag exhibit a reduced frequency of T cells responding to the immunodominant epitope Talpha146-162 indicating a degree of tolerance. We characterized tolerance induction in these animals by analyzing the residual Talpha146-162-responsive T cell population and comparing it to that of nontransgenic littermates. Using CD4(high) sorting, we isolated the vast majority of Ag-reactive T cells from both strains of mice. Quantitative studies of the CD4(high) populations in transgenic mice following immunization with Talpha146-162 revealed a diminished expansion of cells expressing the canonical TCRBV6 but not other TCRBV gene segments when compared with nontransgenic littermates. In addition, CD4(high) cells from transgenic mice were functionally hyporesponsive to Talpha146-162 in terms of proliferation and cytokine secretion regardless of TCRBV gene segment use. TCR sequence analysis of transgenic Vbeta6(+)CD4(high) cells revealed a reduced frequency of cells expressing a conserved motif within the TCRbeta CDR3. Thus, the canonical Talpha146-162 responsive, Vbeta6(+) population demonstrates both quantitative and qualitative deficits that correlate with an altered TCR repertoire whereas the non-Vbeta6 population in transgenic mice exhibits only a reduction in peptide responsiveness, a qualitative defect. These data demonstrate that discrete autoreactive T cell populations with identical peptide/MHC specificity in Torpedo acetylcholine receptor-alpha-transgenic animals bear distinct tolerance imprints.

Evidence of a diverse T cell receptor repertoire for acetylcholine receptor, the autoantigen of myasthenia gravis.

We utilized two methods to look for T cell clonal expansions in myasthenia gravis (MG). We analyzed TCRBV CDR3 length polymorphism (spectratyping) to look for evidence of clonal expansion of CD4 or CD8 T cells directly from peripheral blood of MG patients. No statistically significant differences were found between the diversity of TCR repertoires in MG patients compared to normal control individuals when analyzed as groups. Rare oligoclonal expansions were detected in some individual MG patients but the significance of these findings is unclear. Next, we analyzed a panel of T cell hybridomas from acetylcholine receptor (AChR) immunized, MG-susceptible HLA-DR3 transgenic mice. The epitope specificity, TCRBV gene usage and CDR3 sequences of these hybridomas were highly diverse. We conclude there is only limited evidence for restricted TCR repertoire usage in human MG and suggest this may be due to the inability of HLA-DR molecules to select for restricted TCR recognition of AChR epitopes.

Split tolerance in a novel transgenic model of autoimmune myasthenia gravis.

Because it is one of the few autoimmune disorders in which the target autoantigen has been definitively identified, myasthenia gravis (MG) provides a unique opportunity for testing basic concepts of immune tolerance. In most MG patients, Abs against the acetylcholine receptors (AChR) at the neuromuscular junction can be readily identified and have been directly shown to cause muscle weakness. T cells have also been implicated and appear to play a role in regulating the pathogenic B cells. A murine MG model, generated by immunizing mice with heterologous AChR from the electric fish Torpedo californica, has been used extensively. In these animals, Abs cross-react with murine AChR; however, the T cells do not. Thus, to study tolerance to AChR, a transgenic mouse model was generated in which the immunodominant Torpedo AChR (T-AChR) alpha subunit is expressed in appropriate tissues. Upon immunization, these mice showed greatly reduced T cell responses to T-AChR and the immunodominant alpha-chain peptide. Limiting dilution assays suggest the likely mechanism of tolerance is deletion or anergy. Despite this tolerance, immunization with intact T-AChR induced anti-AChR Abs, including Abs against the alpha subunit, and the incidence of MG-like symptoms was similar to that of wild-type animals. Furthermore, evidence suggests that this B cell response to the alpha-chain receives help from T cells directed against the other AChR polypeptides (beta, gamma, or delta). This model offers a novel opportunity to elucidate mechanisms of tolerance regulation to muscle AChR and to clarify the role of T cells in MG.