Patologia e fisiopatologia generale - infiammazione e tumori prima parte
Humoral immunity, inflammation and cancer Tan and Coussens 213
develop epithelial cancers in the gastrointestinal tract that are not only essential for resolving acute tissue damage
where prominent plasma cell hyperplasia was evident but also essential for promoting tumor development in
adjacent to developing duodenal polyps. Mice harboring initiated tissues.
germline mutations in Smad4 did not exhibit any of these
FcgR and C5a are key regulators of
]. Smad4-deficient T cells
same characteristics [40 IC-mediated inflammation
become skewed in their cytokine profile and prominently Inflammatory responses to ICs have been extensively
express several Th2-type cytokines including IL-4, -5, -6 studied in transgenic mouse models of various auto-
and -13. These pro-tumor mediators also enhance plasma immune diseases . Mechanisms by which ICs initiate
cell differentiation, thus demonstrating that altering local inflammation are still not fully understood; however,
balances of important cytokine pathways, by differential receptors for the Fc portion of IgG (FcgRs, especially
regulation of either HI or CMI, profoundly influences FcgRIII) and complement factors (particularly C5a ana-
malignant risk and argues that perturbing these balances phylatoxin) are recognized as co-dominant effectors in the
to favor anti-tumor immunity represents a powerful anti- process . Considering the fact that tissues damaged by
cancer approach. autoimmune dysfunction and by cancer have similar
ICs have long been suspected as initiators of inflamma- characteristics (e.g. chronic innate immune cell infiltra-
tory cascades associated with tissue destruction in auto- tion, tissue remodeling, angiogenesis, altered cell survival
immune diseases but underlying molecular mechanisms pathways) , it seems probable that similar IC effector
have been elusive . Recent investigations of these pathways are involved in pathogenesis of both diseases.
mechanisms using an experimental mouse model of air-
way remodeling following Mycoplasma pulmonis infection Expressed on most leucocytes, FcgRs are classified into
have demonstrated that peripheral B cell responses and four groups (FcgRI/CD64, FcgRII/CD32, FcgRIII/
local Ig-IC deposition are the critical triggers for recruit- CD16 and recently identified FcgRIV) according to their
ing innate leucocytes into infected airways, that then distinct affinities for IgG, cell distributions and functions.
activate pro-angiogenic and tissue remodeling pathways FcgRI and FcgRIII, predominantly FcgRIII, mediate
necessary for resolving infection . We have reported immune cell activation via their FcR chain that contains
complimentary findings using a transgenic mouse model an intracellular tyrosine-based activating motif (ITAM).
]. Here, oncogenes
of squamous carcinogenesis [43,44 Activating signals mediated by ITAM trigger oxidative
from human papillomavirus type 16 (HPV16) are bursts, cytokine release and phagocytosis by macro-
expressed in skin keratinocytes under direction of a phages, antibody-dependent cell-mediated cytotoxicity
human keratin 14 (K14) promoter/enhancer and initiate (ADCC) by natural killer (NK) cells, and degranulation of
multi-stage development of squamous cell carcinomas mast cells . In contrast, engagement of FcgRIIB that
,45]. In HPV16 trans-
(SCCs) in skin and cervix [43,44 instead contains immune tyrosine-based inhibitory motifs
genic mice, combined B- and T-lymphocyte-deficiency (ITIM) inhibits these same inflammatory responses .
eliminated IC deposition in premalignant skin and atte- These two opposing regulatory pathways coexist on
nuated innate immune cell infiltrations, resulting in innate immune cells and thus, in part, determine the
diminished tissue remodeling activity, failure to activate magnitude of IC-mediated inflammatory responses.
angiogenic vasculature, retention of terminal differen- Indeed, the ratio of activating to inhibitory FcgR is
tiation programs in skin keratinocytes and a 43% reduction low in ’normal’ homeostatic tissues, and by contrast is
]. Adoptive transfer of B-
in overall SCC incidence [44 highly increased in inflamed microenvironments .
lymphocytes or serum isolated from HPV16 mice (but not
from wild-type naı̈ve mice) into B- and T-lymphocyte- Receptors for the Fc portion of IgG, FcgRs play a central
deficient/HPV16 mice restored IC deposition, chronic role in regulating immune responses following interaction
innate immune cell infiltration in pre-malignant skin with ICs . It was recently demonstrated that presence
and reinstated parameters for full malignancy [44 or absence of sialic acid at the terminus of the core glycan in
data indicate that B-lymphocyte-derived factors, possibly the Fc region of IgG regulates immune response [49
Ig, are essential for establishing chronic inflammatory Sialylation of the Fc region of IgG reduces binding affi-
nities towards FcgRs thereby inhibiting pro-inflammatory
pathways that potentiate cancer development. In support activities of IgG, whereas reduction of sialylation, upon
of this concept, anti-tumor antibodies are known to antigen challenge, switches the immune response pathway
enhance outgrowth and invasion of murine and human from anti-inflammatory to pro-inflammatory via differen-
tumor-cell xenografts through recruitment and activation ]. Regu-
tial engagement with FcgRs on effector cells [49
of granulocytes and macrophages , which are important latory functions of FcgRs have been studied using
sources of vascular endothelial growth factor (VEGF)  genetically engineered animal models. Mice deficient in
that possesses pro-angiogenic bioactivities. Thus, serum the FcR chain or activating type FcgRs are resistant to a
proteins (presumably antibodies) produced by B-lympho- g
wide range of IC-mediated hypersensitive reactions, such
cytes locally or peripherally, at least in some scenarios, are as vasculitis, glomerulonephritis and skin Arthus reaction
crucial factors that initiate chronic inflammatory programs,
www.sciencedirect.com Current Opinion in Immunology 2007, 19:209–216
214 Tumour immunology
. Conversely, mice deficient in FcgRIIB exhibit initiate significant pro-tumor effects on developing neo-
enhanced IC-mediated inflammatory responses . plasms. We propose that bolstering anti-tumor cell-
Although these elegant genetic studies demonstrate func- mediated immune responses, in combination with neutra-
tional importance of FcgRs in IC-mediated inflammation lizing potent pro-tumor humoral immune responses with
and autoimmune diseases, little is known about their role in efficacious immuno-therapeutics, would effectively direct
tumor development. tumor suppression while establishing an immune environ-
ment favoring therapeutic responses to conventional anti-
Complement activation is a central event during innate tumor modalities. Certainly, further studies are needed to
immune defence following pathogenic tissue assault. determine the universality of this approach and specifically
Three different pathways of complement activation have which types of human cancers would be amenable to such
been identified, namely classical, alternative and lectin therapy. Nonetheless, a dedicated attempt to reveal the
pathways. Foreign antigens and ICs activate complement molecular and cellular mechanisms linking HI, inflam-
cascades resulting in formation of lytic membrane attack mation and cancer will also provide important insights into
complexes and formation and liberation of anaphylatox- viable therapeutic targets for anti-cancer therapy.
ins; for example, C3a and C5a, potent pro-inflammatory Acknowledgements
factors that induce recruitment and activation of leuko- We acknowledge all the scientists who made contributions to the areas of
cytes. Deposition of complement proteins is a common research reviewed here that were not cited due to space constraints. The
occurrence at sites of inflammation. Studies utilizing authors were supported by grants from the National Institutes of Health
complement depleted mice and C3- or C5-deficient mice (CA72006, CA94168, CA098075), Sandler Program in Basic Sciences,
National Technology Center for Networks and Pathways (U54 RR020843)
have identified their crucial roles in regulating disease and a Department of Defense Era of Hope Scholar Award (BC051640).
pathogenesis [50,51]. We previously reported abundant
deposition of C3 in neoplastic skin of HPV16 mice; but References and recommended reading
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www.sciencedirect.com Current Opinion in Immunology 2007, 19:209–216
+1 anno fa
I contenuti di questa pagina costituiscono rielaborazioni personali del Publisher valeria0186 di informazioni apprese con la frequenza delle lezioni di Patologia e Fisiopatologia Generale e studio autonomo di eventuali libri di riferimento in preparazione dell'esame finale o della tesi. Non devono intendersi come materiale ufficiale dell'università Seconda Università di Napoli SUN - Unina2 o del prof Castoria Gabriella.
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