The Immunologic Constant of Rejection (ICR), is a notion introduced by biologists to group a shared set of genes expressed in tissue destructive-pathogenic conditions like cancer and infection, along a diverse set of physiological circumstances of tissue damage or organ failure, including autoimmune disease or allograft rejection. The identification of shared mechanisms and phenotypes by distinct immune pathologies, marked as a hallmarks or biomarkers, aids in the identification of novel treatment options, without necessarily assessing patients phenomenologies individually.
Concept
The concept of immunologic constant of rejection is based on the proposition that:
Tissue-specific destruction does not necessarily only occur after non-self recognition of the body, but can also occur against self- or quasi-self; such as the phenotypes observed in autoimmune diseases. Immune cells required for the induction of a cognate/adaptive immune response differ from those cells necessary for the activation of an effector immune response. Although the causes of tissue-specific destruction vary among pathologic states, the effector immune response observed in these conditions is found to converge into one single mechanism, including the activation of adaptive and innate cytotoxic mechanisms. Adaptive immunity participates as a tissue-specific trigger, but it is not always sufficient or necessary for tissue destruction. Intensive work on factors activated during immune-mediated rejection have concluded that tissue-specific destruction is correlated with the expression of interferons (IFNa and IFNy), and Interferon-stimulated gene (ISGs).
Mechanism
In the case of autoimmunity and/or allograft rejection, immunity broadens in the target organ by producing chemokines of the CXCL family that recruit the receptor CXCR3-bearing cytotoxic T cells. These initiate the following cascade:
CXCR3 ligand chemokines (CXCL-9, -10 and -11) are produced in response to activated B cells and the pro-inflammatory secretion of interleukin 12 (IL12) and/or interferon-gamma (IFNy) by antigen-presenting cells (APCs). CXCR3 expressing Th1-polarized CD4 T cells and cytotoxic T cells are recruited to the site of acute inflammation. Antigen-activated T cells secrete CCR5 ligands (CCL2 and CCL3) to recruit natural killer (NK) cells and other innate immune effector cells to the site of acute inflammation. Several cytotoxic mechanisms converge on the target tissue, and its complete destruction occurs through the activated effects of CTLs, NK cells, granulocytes, macrophages and dendritic cells.
As such, 20 genes involved in this cascade make up the ICR gene set, including:
T helper type 1 (Th1) cell-related factors such as IFNy, signal transducers and activator of transcription 1 (STAT1), IL12B, Interferon-regulatory factor 1 (IRF1), the transcription factor T-bet (TBX21). CD8 Tcell markers : CD8A & CD8B Immune effector or cytotoxic factors like the granzymes GZMA, GZMB, GZMH, perforin PRF1, and granulysin GNLY. Chemokine ligands CXCL9, CXCL10, and CCL5 that bind to chemokine receptors such as CXCR3 and CCR5, Immune suppressive or counter regulatory genes like IDO1, PDCD1, PDL1 (CD274), CTLA4 and FOXP3
Clinical significance
Cancer
The disrupted homeostasis of cancer cells is found to initiate processes promoting cell growth. To illustrate, growth factors and chemokines activated in response to injury are recruited by tumour cells, sustaining chronic inflammation; similarly to the immune phenotype found in chronic infection, allograft rejection and autoimmunity diseases. The role of immunity in cancer is demonstrated by the predictive and prognostic role of tumour-infiltrating lymphocytes (TIL) and immune response gene signatures. In several cancers these genes show great correlation. A high expression of these genes indicates an active immune engagement, and at least a partial rejection of the cancer tissue.
Breast Cancer
In breast cancer increased survival is observed in patients displaying a high level of ICR gene expression. This immune active phenotype was associated with an increased level of mutations while the poor immune phenotype was defined by perturbation in the MAPK signalling pathways.