Immunology series最新文献

The ovine and caprine lentiviruses infect monocytes, and the viral DNA is integrated into the cellular DNA. The provirus remains silent until the monocyte matures into a macrophage. Intrinsic to this maturation is the induction of a class of immediate early genes in the monocyte that includes the transcription factors JUN and FOS. These transcription factors are thought to couple short-term signals in the cell to long-term cellular differentiation by regulation of specific cellular genes. Thus, JUN and FOS bind to the AP-1 site in the promoters of cellular genes and activate their transcription, resulting in maturation of the monocyte into a macrophage. In addition, these cellular factors activate the same AP-1 sequence in the visna virus LTR, leading to transcriptional activation, full viral gene expression, and production of progeny virus. The expression of viral antigens in the context of MHC class II on the macrophage leads to the production of cytokines and a lymphoproliferative response that causes the lesions in specific target organs in an infected animal. We still understand only the framework of these events. The specific mechanisms by which viral genes alter macrophage gene expression and the molecular basis of different viral tropism for specific tissue macrophages, i.e. microglia, remain to be determined.

Various lines of defense against infection are present in all living creatures. The balance between symbiosis and parasitism is determined by the mechanisms through which the host resists infection and by the extent of injury induced by the parasite: both factors contribute to disease. Lines of host defense can be arbitrarily divided into three components: 1) barrier functions of skin and mucous membranes and their innate physical and secretory antimicrobial components; 2) elements of host defense that do not necessarily require prior exposure to an infectious agent or immunologic memory (mast cells, granulocytes, macrophages, NK cells, gamma/delta T cells); and 3) immune responses directed against specific epitopes on the infectious agent induced by prior exposure and immunologic memory (alpha/beta T cells, B cells). Analysis of such host defense mechanisms repeatedly documents tremendous redundancy and overlap between these lines of defense. Further, there is open communication, so that a change at any one level ripples throughout the system. Acquired nonspecific resistance to infection is an example of such a ripple. Host response to one infection alerts the immune system, so that the general level of resistance to other infectious agents is increased. This response is initiated by an immune response (third line of defense) but effected by nonspecific elements (second line of defense). The survival value of such responses is obvious. There are numerous examples in both mouse and man of the operation of these systems in response to infection. Further, the menus of antimicrobial components available to both mouse and man for resistance to infection are very similar, but not identical. Indeed, it is said that the genetic basis for differences between mice and man revolve around a difference of less than 10% in DNA sequences. But there are differences! Mouse macrophages produce IFN-beta in response to infection, human cells produce IFN-alpha. Mouse macrophages effect antimicrobial activity principally through induction of NO synthase and the generation of toxic nitrogen oxides. This pathway has yet to be described with human macrophages. In both man and mouse, F. tularensis is an obligate intracellular parasite of macrophages that requires an essential component provided by the cell for its replication. That mouse and man are not so different is well illustrated by the effector mechanisms induced by IFN-gamma for antimicrobial activity against F. tularensis.(ABSTRACT TRUNCATED AT 400 WORDS)

Macrophages are a heterogeneous population that vary depending on their species of origin, anatomic location, state of activation, and conditions of culture. Moreover, macrophages normally interact with other cells both within and without the immune system. It is clear from the data reviewed in this chapter that all of these aforementioned variables greatly influence macrophage-C. neoformans interactions. While circumstantial evidence strongly supports a major role for the macrophage in host defenses against cryptococcosis, the nature and extent of the contribution macrophages make remain to be defined. One major challenge for researchers in this field will be to design experiments that closely mimic what occurs in human physiological and pathological states.