Polysaccharide-Specific Memory B Cells Predict Protection against Experimental Human Pneumococcal Carriage.

RATIONALE: We have previously demonstrated that experimental pneumococcal carriage enhances immunity and protects healthy adults against carriage reacquisition after rechallenge with a homologous strain. OBJECTIVES: To investigate the role of naturally acquired pneumococcal protein and polysaccharide (PS)-specific immunity in protection against carriage acquisition using a heterologous challenge model. METHODS: We identified healthy volunteers that were naturally colonized with pneumococcus and, after clearance of their natural carriage episode, challenged them with a heterologous 6B strain. In another cohort of volunteers we assessed 6BPS-specific, PspA-specific, and PspC-specific IgG and IgA plasma and memory B-cell populations before and 7, 14, and 35 days after experimental pneumococcal inoculation. MEASUREMENTS AND MAIN RESULTS: Heterologous challenge with 6B resulted in 50% carriage among volunteers with previous natural pneumococcal carriage. Protection from carriage was associated with a high number of circulating 6BPS IgG-secreting memory B cells at baseline. There were no associations between protection from carriage and baseline levels of 6BPS IgG in serum or nasal wash, PspA-specific, or PspC-specific memory B cells or plasma cells. In volunteers who did not develop carriage, the number of circulating 6BPS memory B cells decreased and the number of 6BPS plasma cells increased postinoculation. CONCLUSIONS: Our data indicate that naturally acquired PS-specific memory B cells, but not levels of circulating IgG at time of pneumococcal exposure, are associated with protection against carriage acquisition.

Are SSRIs responsible for precipitating suicidal ideation in teenagers with 'subsyndromal' bipolar affective disorder who have been misdiagnosed with unipolar depression?

Concerns have recently been raised about a possible link between suicidal ideation and the use of SSRIs in teenagers diagnosed with unipolar depression, such that the USA FDA and UK CSM have issued warnings regarding the use of SSRIs in adolescents with depression. We investigated this phenomenon first by recognizing that the initial presentation of unipolar and bipolar depression may only differ in subtle ways and with the result being that a significant number of patients are misdiagnosed at the expense of patient outcomes. This is especially pertinent as patients with bipolar disorder have increased lifetime rates of suicide as compared with those patients with unipolar depression. The normal developmental trajectory of bipolar disorder often involves recurrent depressive episodes in early adolescence before the development of hypomanic/manic episodes. Therefore, a misdiagnosis of bipolar disorder as unipolar depression in teenagers could explain the failure of SSRIs to adequately treat depressive episodes. A suboptimal response to SSRIs and so a lack of control of the depression is a risk factor for suicide. One reason for this suboptimal response is the markedly different neurotransmission involved in bipolar depression as compared to the neurotransmitter systems operated on by SSRIs. In bipolar disorder, dopamine is the principal neurotransmitter disrupted and we marshal structural, pharmacological and biochemical evidence to support this claim. One important strand of evidence involves polymorphisms in D1 and D2 dopamine receptors being implicated in the pathogenesis of bipolar affective disorder. Serotonin neurotransmission is affected by SSRIs, however the role of serotonin in bipolar disorder is much more ambiguous. The conclusion we arrive at is that the link between suicidality and SSRI use in adolescents diagnosed with unipolar depression may in fact be due to inappropriate treatment of misdiagnosed bipolar disorder that has yet to manifest with hypomanic/manic symptoms.