Forum on Immunopathological Diseases and Therapeutics

The immune response is a cornerstone in the body's struggle against microbial pathogens. In ways that we do not yet completely understand, the mammalian immune response has evolved to identify proteins of pathogens that are either important virulence factors or key immunoprotective targets. Professor James N. Miller suggested that one way to discover such proteins is to harness the power of the immune system in the laboratory.This general concept, referred to here as the Miller Hypothesis, took several different manifestations in the discovery of some of the best known and widely studied leptospiral proteins: The porin OmpL1 was identified by surface immunoprecipitation, leptospiral immunoglobulin-like proteins were uncovered by screening a genomic library with sera from leptospirosis patients, and the major outer-membrane lipoprotein LipL32 was recognized through immunoblot studies...

Chlamydia pneumoniae , an obligate intracellular bacterial pathogen, has long been investigated as a potential developmental or exacerbating factor in various pathologies. Its unique lifestyle and ability to disseminate throughout the host while persisting in relative safety from the immune response has placed this obligate intracellular pathogen in the crosshairs as a potentially mitigating factor in chronic inflammatory diseases. Many animal model and human correlative studies have been performed to confirm or deny a role for C...

The introduction of immunopathologic reaction classification in the 1960s led to a major advance in understanding immune effector mechanisms and how lesions of immunopathologic diseases developed. In this article, immunopathologic mechanisms are presented for experimental models of syphilis, influenza, and asthma. The chancre of syphilis is a delayed hypersensitivity skin reaction that is initiated by sensitized T cells that activate macrophages to phagocytose and kill the infecting organism, Treponema pallidum , in interstitial tissues...

Borrelia burgdorferi , the spirochete that causes Lyme disease, exists in an enzootic cycle, alternating between a tick vector and a vertebrate host. To adapt to and survive the environmental changes associated with its enzootic cycle, including nutrient availability, B. burgdorferi uses three different systems to regulate the expression of genes: RpoN-RpoS, histidine kinase (Hk)1/response regulator 1 (Rrp1), and RelBbu . The RpoN-RpoS alternative sigma factor cascade activates genes required for transmission from the tick to the vertebrate, maintenance of the vertebrate infection, and persistence in the tick...

Borrelia burgdorferi is the causative bacterial agent of Lyme disease, the most prevalent tick-borne infection in North America. The ability of B. burgdorferi to cause disease is highly dependent on its capacity to evade the immune response during infection of the mammalian host. One of the ways in which B. burgdorferi is known to evade the immune response is antigenic variation of the variable major protein (VMP)-like sequence (Vls) E lipoprotein. Past research involving the B. burgdorferi antigenic variation system has implicated a gene-conversion mechanism for vlsE recombination, analyzed the long-term dynamic changes occurring within VlsE, and established the critical importance of antigenic variation for persistent infection of the mammalian host...

Premature infants are at increased risk for morbidity and mortality due to necrotizing enterocolitis (NEC) and sepsis. Probiotics decrease the risk of NEC and death in premature infants; however, mechanisms of action are unclear. A wide variety of probiotic species have been evaluated for potential beneficial properties in vitro, in animal models, and in clinical trials of premature infants. Although there is variation by species and even strain, common mechanisms of protection include attenuation of intestinal inflammation, apoptosis, dysmotility, permeability, supplanting other gut microbes through production of bacteriocins, and more effective use of available nutrients...

During the last decade, probiotics have been established to be important mediators of host immunity. Their effects on both innate and adaptive immunity have been documented in the literature. Although several reports have correlated different strains of bacteria as probiotics, their effects on immunity vary. Clearly, there is a complex interplay between various constituents of probiotics and the immune response in humans. The role of probiotics on natural killer (NK) cells in the gut has been the subject of a few reports...

The Krüppel-like factor 4 (KLF4) gene is located on chromosome 9q31. All of the currently known 17 KLF transcription regulators that have similarity with members of the specificity protein family are distinctly characterized by the Cys2/His2 zinc finger motifs at their carboxyl terminals for preferential binding to the GC/GT box or the CACCC element of the gene promoter and enhancer regions. KLF4 is a transcriptional regulator of cell proliferation, differentiation, apoptosis, migration, and invasion, emphasizing its importance in diagnosis and prognosis of particular tumors...

John Fahey was an integral member of the small group of investigators who developed the Multicenter AIDS Cohort Study (MACS) in the early 1980s. A major research theme in the MACS was defining immune system changes in men at risk for developing AIDS. John's experience and expertise provided a solid grounding for the immunologic investigations conducted in the MACS. Additionally, he contributed enormously to the science of the MACS and pioneered the critical evaluation of serologic methods of documenting infection with HIV and T cell phenotyping...

HIV infection is associated with a greatly elevated risk for the development of non-Hodgkin lymphoma (NHL), which while diminished, remains elevated in the highly active antiretroviral therapy (HAART) era. Chronic B cell activation, driven by contact with HIV virions, B cell-stimulatory cytokines, viruses (EBV, HPV, HCV), and by high levels of antigenic stimulation occurs in HIV infected persons, and it is seen at even higher levels in those who go on to develop AIDS-NHL. Evidence from multiple studies indicates that elevated serum levels of several B cell-stimulatory cytokines and biomarkers are seen preceding AIDS-NHL, as well as in immunocompetent persons that develop NHL...

Emigration of mature naïve CD4 SP T cells from the human thymus to the periphery is not fully understood, although elucidation of the mechanisms that govern egress of T cells is crucial to understanding both basic immunology and the immune response in diseases such as HIV infection. Recent work has brought to light the requirement for sphingosine-1-phosphate (S1P) and its receptors in a variety of fields including mature naïve T-cell egress from the thymus of mice. We are examining the expression and function of this novel requisite T-cell egress receptor within the human thymus, characterizing changes observed in the expression and function of this receptor in infectious diseases...

Extracellular vesicles, including microvesicles, exosomes and apoptotic bodies are recognized as carriers of pathogen-associated molecules with direct involvement in immune signaling and inflammation. Those observations have enforced the way these membranous vesicles are being considered as promising immunotherapeutic targets. In this review, we discuss the emerging roles of extracellular vesicles in autoimmunity and highlights their potential use as disease biomarkers as well as targets for the treatment and prevention of autoimmune diseases...

Chronic asymptomatic worm infection, often in combination with tuberculosis (TB), is common in low-income countries. Indeed, a life without worm infestation, as is now the case in most high-income countries, is a recent condition for humankind. Worms and Mycobacterium tuberculosis give rise to different immune response patterns (Th2 vs. Th1 driven), and we have studied whether chronic worm infection affects the susceptibility to and control of TB in the low income country of Ethiopia. Our results, as well of those in the general literature, are inconclusive, although we have some rather strong data in support of adult deworming in relation to vaccination with bacillus Calmette-Guérin (BCG) against TB...

Despite the success of combination antiretroviral therapy (cART), a latent viral reservoir persists in HIV-1-infected persons. Unfortunately, endogenous cytotoxic T lymphocytes (CTLs) are unable to control viral rebound when patients are removed from cART. A "kick and kill" strategy has been proposed to eradicate this reservoir, whereby infected T cells are induced to express viral proteins via latency-inducing drugs followed by their elimination by CTLs. It has yet to be determined if stimulation of existing HIV-1-specific CTL will be sufficient, or if new CTLs should be primed from naïve T cells...

Measurement of circulating cytokine levels can provide important information in the study of the pathogenesis of disease. John L. Fahey was a pioneer in the measurement of circulating cytokines and immune-activation markers and a leader in the quality assessment/control of assays for measurement of circulating cytokines. Insights into the measurement of circulating cytokines, including consideration of multiplex assays, are presented here.

T-cell exhaustion due to persistent antigen stimulation is a key feature of chronic viral infections and cancer. Programmed cell death-1 (PD-1) is a major regulator of T-cell exhaustion, and blocking the PD-1 pathway restores T-cell function and improves pathogen control and tumor eradication. Immunotherapy targeting the PD-1 inhibitory receptor pathway has demonstrated significant antitumor activity. Recently, antibodies blocking PD-1 have been approved for use in cancer patients. In this review, we summarize the role of the PD-1 pathway in chronic infection and cancer and the therapeutic potential of PD-1-directed immunotherapy in patients with chronic infection or cancer...

John Fahey was one of the first investigators to study the then-new acquired immune deficiency syndrome (AIDS). He made major contributions to the design of the Multicenter AIDS Cohort Study (MACS), and vigorously promoted novel and high-quality science as the MACS evolved. His contributions are highly valued.

Antiretroviral therapy (ART) can reduce HIV viral loads to undetectable levels and prevent disease progression. However, HIV persists in rare cellular reservoirs within ART-treated patients and rapidly reemerges if ART is stopped. Latently infected CD4(+) T cells represent a major reservoir of HIV that persists during ART. Therefore, a cure for HIV must include methods that either permanently inactivate or eliminate latent virus. Experimental methods under investigation for eliminating latently infected cells include transplantation/gene therapy approaches intended to deplete the infected cells and replace them with HIV-resistant ones, and DNA editing strategies that are capable of damaging or excising non-expressing HIV proviruses...

Foundational cellular immunology research of the 1960s and 1970s, together with the advent of monoclonal antibodies and flow cytometry, provided the knowledge base and the technological capability that enabled the elucidation of the role of CD4 T cells in HIV infection. Research identifying the sources and magnitude of variation in CD4 measurements, standardized reagents and protocols, and the development of clinical flow cytometers all contributed to the feasibility of widespread CD4 testing. Cohort studies and clinical trials provided the context for establishing the utility of CD4 for prognosis in HIV-infected persons, initial assessment of in vivo antiretroviral drug activity, and as a surrogate marker for clinical outcome in antiretroviral therapeutic trials...

NF-κB has long been known to play an important role in autoimmune diseases such as rheumatoid arthritis (RA). Indeed, as our understanding of how NF-κB is utilized has increased, we have been hard put to find a process not associated with this transcription factor family in some way. However, new data originating, in part, from genome-wide association studies have demonstrated that very specific alterations in components of the NF-κB pathway are sufficient to confer increased risk of developing disease. Here we review the data which have identified specific components of the NF-κB pathway, and consider what is known of their mechanisms of action and how these mechanisms might play into the disease process...