Page 455 - Clinical Immunology_ Principles and Practice ( PDFDrive )

434 ParT THrEE Host Defenses to Infectious Agents

IL-15, produced by activated monocytes, stimulates NK-cell Trichomonas vaginalis
proliferation, cytotoxicity, and cytokine production, including
IFN-γ. There is significant IL-15 expression in the jejunal mucosa Pathogenesis
in immunocompetent patients with cryptosporidiosis, and IL-15 Trichomonas vaginalis is a flagellated protozoan parasite of the
levels inversely correlate with parasite burden. However, in patients human urogenital tract that exists only as a trophozoite. It causes
with AIDS who have chronic uncontrolled cryptosporidiosis, vaginitis, cervicitis, and urethritis. Its adherence to the vaginal
IL-15 is undetectable. 33 squamous epithelium is facilitated by a number of adhesins.
Mannose-binding lectin (MBL) is a serum protein that binds Trichomonas causes tissue damage by contact-dependent cytolysis
to various pathogens, including Cryptosporidium. Upon binding, caused by pore-forming proteins and proteases, and secretion
MBL activates complement, thereby promoting opsonization of a glycoprotein cell-detaching factor that causes sloughing of
and phagocytosis. Low serum levels of MBL, which may result the vaginal epithelium. Levels of the cell-detaching factor correlate
from malnutrition or polymorphisms in the MBL2 gene, increase with the severity of the disease, and vaginal antibodies directed
33
susceptibility to cryptosporidiosis. Infected intestinal cells also against this factor modulate its effects. Inflammation in the genital
release TGF-β, which decreases necrosis and stimulates the mucosa and submucosa leads to copious secretions, and the
synthesis of extracellular matrix proteins, thereby limiting surface epithelium may slough, causing focal erosions and
epithelial damage. hemorrhage.
Prostaglandins E 2 and F 2 α, released by infected enterocytes, The increased risk of HIV transmission in women with
not only promote secretory diarrhea but also upregulate mucin trichomoniasis may result from increased recruitment of inflam-
production, which may hinder parasite attachment. In addition, matory cells, mucosal erosion, or degradation of secretory
these prostaglandins stimulate the release of β-defensin-2, which leukocyte protease inhibitor (SLPI) by trichomonal proteases.
has direct anticryptosporidial activity and is chemotactic for T Lower levels of SLPI are found in the vaginal fluid of women
cells and DCs. 33 with trichomoniasis, which can lead to increased tissue damage
36
and HIV transmission. The lipophosphoglycan of Trichomonas
Adaptive Immunity induces production of the chemokines IL-8 and CCL20, which,
Cell-mediated immunity plays an important role the resolution which can also facilitate HIV infection by promoting DC
of cryptosporidiosis and protection from reinfection. In immu- recruitment.
nocompetent, adult mice CD4 intraepithelial lymphocytes (IELs)
initiate early control of infection, whereas cytotoxic CD8 IELs Innate Immunity
appear later and function in parasite elimination. Resolution of Although trichomoniasis has recently received increased attention
infection depends on a balance of Th1 cytokines (IFN-γ, IL-18) as a risk factor for HIV transmission and obstetrical complications,
needed to control the infection and Th2 cytokines (IL-4, IL-10, there is little known about the protective immune response against
and IL-13) that limit immunopathological damage. In mice, γδ this organism. Trichomonas secretes a factor that promotes
T cells are rapidly recruited to control cryptosporidial infection, neutrophil chemotaxis, causing profuse leukorrhea, but the
but their role in human infection is unknown. Severe intestinal oxidative microbicidal mechanisms of the neutrophils have
disease or biliary involvement is usually seen in patients with decreased efficacy in the anaerobic vaginal environment. Activated
33
AIDS whose CD4 count is <50/µL. Patients with HIV infection macrophages can destroy trichomonads in a T and B cell–
who have CD4 counts >200/µL usually experience self-limited independent manner and release IL-lβ and TNF-α, which are
37
disease. chemotactic for neutrophils. Trichomonas induces neutrophil
The role of humoral immunity is less clear. Secretory antibodies apoptosis, and macrophage clearance of these apoptotic cells
produced in the intestines are thought to impair parasite attach- causes release of IL-10, which may contribute to resolution of
ment to epithelial cells. Indeed, immunoglobulin deficiencies the inflammatory response. 38
are often associated with persistent or recurrent infections.
However, specific anti-Cryptosporidium IgA levels have been Adaptive Immunity
reported in patients with AIDS who are infected with the parasite, Repeated infections with T. vaginalis do not induce immunity;
suggesting polyreactive T cell–independent antibodies are not however, the infection is self-limited in most cases, so there are
33
sufficient for parasite eradication. In experimentally infected effective mechanisms of host defense. T. vaginalis induces the
human volunteers, serum IgM and IgG directed toward sporozoite production of antibodies in both the serum and vaginal secretions.
proteins protect against the development of symptoms, but not The serum antibody response correlates with active infection,
infection. and serum, but not vaginal, IgG from infected patients displays
complement-mediated lytic activity against trichomonads in
Evasion of Host Immunity culture. 38
Cryptosporidium evades host defenses primarily by exerting control
over infected enterocyte apoptosis. One of the upregulated genes Evasion of Host Immunity
is osteoprotegerin, which inhibits apoptosis by acting as a decoy Although T. vaginalis activates the alternative pathway of comple-
34
receptor for TNF-related apoptosis inducing ligand (TRAIL). ment, the cervical mucus and menstrual blood are low in comple-
Control of host apoptosis is complex; early inhibition of apoptosis ment. Menstrual blood also supplies iron, which upregulates
by NF-κB activation allows the parasite to complete its life cycle, trichomonal adhesins and cysteine proteases, causing the degrada-
whereas the late promotion of apoptosis facilitates merozoite tion of complement component C3 bound to the surface of the
release. Nevertheless, the infected cells secrete FasL, which parasite. Parasite virulence is thus enhanced, and the symptoms
promotes apoptosis in uninfected bystander cells. In this way, are exacerbated during menses. Cysteine proteases secreted by
the host counters the antiapoptotic activity of the parasite by T. vaginalis also degrade immunoglobulins, sabotaging the
surrounding the parasitized cells by a zone of apoptotic cells. antibody response. The parasite also secretes soluble antigens