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Advanced Immunology: Signaling Pathways, Transplant Rejection, and Tumor Immunology

← Builds on Immune Disorders: Immunodeficiencies, Autoimmunity, and Hypersensitivities

Terms you will need

  • jak-stat pathwayThe JAK-STAT pathway is a system inside cells that helps control processes like immunity, cell division, and cell death by passing signals from outside the cell to the nucleus, where genes are turned on or off. (chunk id: anatomy-and-physiology--advanced_immunology--en_jak_stat_signaling_pathway--000)
  • cgas-sting pathwayThe cGAS-STING pathway is part of the body's first line of defense that detects DNA in the wrong place in cells, like from a virus or damaged cells, and triggers an immune response to fight it. (chunk id: anatomy-and-physiology--advanced_immunology--en_cgas_sting_cytosolic_dna_sensing_pathway--000)
  • hyperacute rejectionHyperacute rejection is a fast immune reaction that happens right after a transplant when the recipient's body has already made antibodies against the donor organ, causing quick damage. (chunk id: anatomy-and-physiology--advanced_immunology--en_transplant_rejection--000)
  • acute rejectionAcute rejection is an immune reaction that happens weeks to months after a transplant, where the recipient's immune system attacks the donor organ using special white blood cells. (chunk id: anatomy-and-physiology--advanced_immunology--en_transplant_rejection--000)
  • graft-versus-host diseaseGraft-versus-host disease is a condition where the immune cells from the donor in a transplant attack the recipient's body, mistaking it for foreign. (chunk id: anatomy-and-physiology--advanced_immunology--en_graft_versus_host_disease--000)

How this topic runs

  1. 1Start here
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Advanced immunology explores complex biological processes that regulate immune responses, including signaling pathways, transplant rejection, and tumor immunology. The JAK-STAT signaling pathway is a key mechanism in immune signaling, influencing processes like cell division, death, and immune response. Disruptions in this pathway can lead to diseases such as cancer and immune disorders. Transplant rejection occurs when the immune system attacks transplanted tissue, and it is categorized into hyperacute, acute, and chronic forms. Understanding these rejection types helps in developing strategies to prevent or manage them. Tumor immunology examines how the immune system detects and responds to cancer, including pathways like the cGAS-STING pathway, which helps detect cytosolic DNA and trigger immune responses.

Figures (10)

Key steps of the JAK-STAT pathway. JAK-STAT signalling is made of three major proteins: cell-surface receptors, Janus kinases (JAKs), and signal transducer and activator of transcription proteins (STATs). Once a ligand (red triangle) binds to the receptor, JAKs add phosphates (red circles) to the receptor. Two STAT proteins then bind to the phosphates, and then the STATs are phosphorylated by JAKs to form a dimer. The dimer enters the nucleus, binds to DNA, and causes transcription of target genes. The JAK-STAT system consists of three main components: (1) a receptor (green), which penetrates the cell membrane; (2) Janus kinase (JAK) (yellow), which is bound to the receptor, and; (3) Signal Transducer and Activator of Transcription (STAT) (blue), which carries the signal into the nucleus and DNA. The red dots are phosphates. After the cytokine binds to the receptor, JAK adds a phosphate to (phosphorylates) the receptor. This attracts the STAT proteins, which are also phosphorylated and bind to each other, forming a pair (dimer). The dimer moves into the nucleus, binds to the DNA, and causes transcription of genes. Enzymes that add phosphate groups are called protein kinases.[5]
An example of the integration between JAK-STAT, MAPK/ERK and PI3K/AKT/mTOR signalling pathways. JAKs phosphorylate cytokine receptors which can bind a protein called Grb2. Grb2 then activates SOS proteins which stimulate MAPK signalling. MAPK can also phosphorylate STATs. Phosphorylated cytokine receptors can also be bound by PI3K, which allows activation of AKT. ERK, STATs and Akt can then interact with other proteins. The receptor is not shown as a dimer, and only one side of the receptors are shown phosphorylated for simplification
Three ways PIAS proteins can inhibit JAK-STAT signaling. (A) Adding a SUMO group to STATs can block their phosphorylation, which prevents STATs entering the nucleus. (B) HDAC (histone deacetylase) recruitment can remove acetyl modifications on histones, lowering gene expression. (C) PIAS can also prevent STATs binding to DNA
Psoriasis on the hands can be caused by faulty JAK-STAT signalling.
Cytokine release via activation of JAK/STAT signalling pathway following SARS-Cov-2 infection resulting in ARDS related to COVID-19.[68]
Micrograph showing a glomerulus with changes characteristic of a transplant glomerulopathy. Transplant glomerulopathy is considered a form of chronic antibody-mediated rejection. PAS stain.
Micrographs of grades of skin graft-versus-host disease: Ranging from grade I GvHR (with minimal vacuolization in the epidermis) to grade II GvHR (with vacuolization and dyskeratotic bodies) to grade III GvHR (with sub epidermal cleft formation) and finally to grade IV GvHR (with separation of the dermis from the epidermis)[2]
GvHD pathology
cGAS bound to dsDNA. Adapted from PDB 4O6A.[10]
STING bound to cGAMP. While STING exists as a homodimer, only one subunit is shown to highlight the interaction of side chain residues with cGAMP. Adapted from PDB 4KSY[15]

It starts when proteins called JAKs and STATs respond to signals from outside the cell, like cytokines. These signals lead to changes in gene activity in the cell nucleus. Problems in this pathway can cause diseases like cancer and immune disorders.

This pathway is especially important in immune cells, where it helps control how the body reacts to infections and other threats. Transplant rejection happens when the immune system attacks a new organ or tissue. It is divided into three types: hyperacute, acute, and chronic.

Hyperacute rejection is fast, happening within minutes, and is caused by antibodies the recipient already has. Acute rejection occurs weeks to months after the transplant and involves T-cells recognizing the donor tissue as foreign. Chronic rejection is slower and leads to long-term damage.

Preventing rejection often involves matching donor and recipient tissues and using drugs to suppress the immune system. The cGAS-STING pathway helps the immune system detect DNA in the wrong place, like in the cell’s cytoplasm. This often happens during infections or in cancer.

When cGAS finds DNA, it makes a molecule called cGAMP, which activates STING. This leads to the production of interferons and other immune signals. This pathway is important for fighting viruses and tumors.

It also plays a role in autoimmune diseases when the immune system mistakenly attacks the body’s own DNA. Understanding this pathway helps scientists develop better treatments for infections and cancer.

Key Points

  • The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumor formation.
  • The cGAS–STING pathway (cyclic GMP-AMP synthase - stimulator of interferon genes) is a component of the innate immune system that functions to detect the presence of cytosolic DNA and, in response, trigger expression of inflammatory genes that can lead to senescence or to the activation of defense mechanisms.
  • Hyperacute rejection is a form of rejection that manifests itself in the minutes to hours following transplantation.
  • Acute rejection is a category of rejection that occurs on the timescale of weeks to months, with most episodes occurring within the first 3 months to 1 year after transplantation.
  • Chronic rejection is an insidious form of rejection that leads to graft destruction over months to years after tissue transplantation.
  • Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs.

Terms

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