The immune system, a complex and sophisticated defense mechanism, is crucial for maintaining health and fighting diseases. It is broadly categorized into two distinct yet interrelated systems: the innate immune system and the adaptive immune system.

Innate Immune System

The innate immune system, often referred to as the "nonspecific" immune system, is the body's first line of defense against pathogens. It acts promptly, providing a general but rapid response to a wide range of foreign substances. The innate immune system comprises several components, including physical barriers like skin and mucous membranes, immune cells such as natural killer cells and macrophages, and proteins that support the immune response.

Notably, the innate immune system operates through various cell signaling pathways, such as the angiopoietin-TIE2, GSK3, and CCR5 pathways in macrophages. These pathways play vital roles in immune response regulation, pathogen clearance, and homeostasis maintenance. Dysregulation of these pathways can lead to diseases, including autoimmune disorders and cancer.

Innate Immunity Pathways

The angiopoietin-TIE2 signaling pathway, GSK3 signaling pathway, and CCR5 pathway are all involved in innate immunity cell signaling pathways, including macrophages. The angiopoietin-TIE2 signaling pathway involves the angiopoietins, a family of growth factor ligands that bind to TIE2/Tek TRK (Receptor Tyrosine Kinase). This pathway mediates cell motility through activation of the Phosphatidylinositol-3 Kinase pathway and the Ras pathway. The GSK3 signaling pathway is a ubiquitously expressed, highly conserved serine/threonine protein kinase found in all eukaryotes. It is involved in the regulation of various cellular processes, including cell proliferation, differentiation, and apoptosis. The CCR5 pathway is a member of the chemokine receptor subclass of the GPCR (G-Protein-Coupled Receptor) superfamily. It is involved in the regulation of immune cell migration and activation. Dysregulation of these pathways can lead to various diseases, including autoimmune diseases and cancer. These pathways are important for the innate immune system's function, including macrophages, which play a crucial role in the immune response to pathogens and tissue repair.

Innate Immunity Pathways

The angiopoietin-TIE2 signaling pathway, GSK3 signaling pathway, and CCR5 pathway are all involved in innate immunity cell signaling pathways, including macrophages. The angiopoietin-TIE2 signaling pathway involves the angiopoietins, a family of growth factor ligands that bind to TIE2/Tek TRK (Receptor Tyrosine Kinase). This pathway mediates cell motility through activation of the Phosphatidylinositol-3 Kinase pathway and the Ras pathway. The GSK3 signaling pathway is a ubiquitously expressed, highly conserved serine/threonine protein kinase found in all eukaryotes. It is involved in the regulation of various cellular processes, including cell proliferation, differentiation, and apoptosis. The CCR5 pathway is a member of the chemokine receptor subclass of the GPCR (G-Protein-Coupled Receptor) superfamily. It is involved in the regulation of immune cell migration and activation. Dysregulation of these pathways can lead to various diseases, including autoimmune diseases and cancer. These pathways are important for the innate immune system's function, including macrophages, which play a crucial role in the immune response to pathogens and tissue repair.

Key components of the innate immune system include the NF-κB pathway, Toll-Like Receptors (TLRs), and the Complement system. The NF-κB pathway plays a central role in regulating genes associated with inflammation and immune responses. TLRs recognize molecular patterns on pathogens and trigger immune responses. The Complement system, comprising over 30 proteins, assists in opsonization, inflammation, and pathogen elimination through different activation pathways. These systems are interrelated and collectively form the frontline defense of the innate immune response.

The JAK-STAT pathway is integral to immune regulation, involved in various functions such as fighting infection, immune tolerance, and barrier functions. It consists of JAK kinases and STAT transcription factors, which are activated by cytokines, leading to gene expression regulation. Dysregulation in this pathway is associated with immune disorders, highlighting its significance in immune regulation.

Adaptive Immune System

The adaptive immune system is engaged when the innate system is insufficient to eliminate pathogens. It is characterized by its ability to recognize specific "non-self" antigens and distinguish them from "self" antigens. This specificity leads to a tailored immune response against specific pathogens, contributing to long-lasting immunity.

The adaptive immune system is also involved in the development of autoimmune diseases, where the immune system erroneously targets the body's own cells.

Adaptive Immune System: VDJ Recombination and HLA Genes

VDJ recombination and HLA genes are both involved in the adaptive immune system's function. VDJ recombination is a DNA rearrangement process that generates the diversity of T and B lymphocyte immune repertoire. It proceeds through the generation of a DNA double-strand break (DNA-DSB) by the Rag1/2 lymphoid-specific factors, which is repaired by the non-homologous end joining (NHEJ) DNA repair pathway. HLA genes encode major histocompatibility complex (MHC) proteins that present antigens to T cells, helping them recognize foreign substances and mount an immune response. The AIRE HLA antigen-presenting pathway is essential for maintaining immune tolerance and preventing autoimmune diseases. The VDJ recombination process generates a diverse repertoire of antigen receptors (AgR) in the adaptive immune system, which are capable of recognizing a vast array of foreign antigens. V(D)J recombinase specificity guides AgR gene assembly by dictating gene segment utilization in developing B- and T-cells. Gene segments within the same class, such as VH gene segments, are not equally utilized during V(D)J recombination, resulting in biased AgR expression.

The fidelity of V(D)J recombination affects the immune system in several ways:

1. Diversity of antigen receptors: V(D)J recombination is an essential mechanism for generating a diverse set of antigen receptors in developing T and B cells. The imprecision of aspects of the joining reaction contributes significantly to increasing the variability of the resulting functional genes. This diversity is crucial for the immune system to recognize and respond to a wide range of foreign antigens.
2. Immune system development: The efficiency and fidelity of V(D)J recombination play a role in the development of the immune system. For example, the severity of the effect on immune system development can be reduced when the efficiency and fidelity of V(D)J recombination are compromised.
3. Genome instability and lymphoid malignancy: The association of antigen receptor genes with active or inactive nuclear compartments and changes in the higher-order chromatin architecture of antigen receptor genes can influence the targeting and mistargeting of V(D)J recombination. This can contribute to genome instability and lymphoid malignancy.
4. Somatic hypermutation and class switch recombination: V(D)J recombination is also involved in somatic hypermutation and class switch recombination of immunoglobulins. These processes are essential for generating a diverse repertoire of antibodies and for the class switching of immunoglobulins during B cell maturation.

AIRE Self Antigen Recognizing Pathway

The AIRE self antigen recognizing pathway is involved in the adaptive immune system and plays a crucial role in maintaining immune tolerance and preventing autoimmune diseases. AIRE (Autoimmune Regulator) is a transcription factor that regulates the expression of HLA genes, which encode major histocompatibility complex (MHC) proteins. MHC proteins present antigens to T cells, helping them recognize foreign substances and mount an immune response. The AIRE self antigen recognizing pathway involves several steps:

1. AIRE is expressed in medullary thymic epithelial cells (mTECs) and drives the negative selection of self-recognizing T cells.
2. AIRE initiates the transcription of a wide selection of organ-specific genes that create proteins that are usually only expressed in peripheral tissues, creating an "immunological self-shadow" in the thymus.
3. T cells with receptors that recognize the body's own proteins need to be eliminated while still in the thymus. Through the action of AIRE, mTECs express major proteins from elsewhere in the body (so-called "tissue-restricted antigens" - TRA) and T cells that respond to those proteins are eliminated through cell death (apoptosis).
4. When AIRE is defective, T cells that recognize antigens normally produced by the body can exit the thymus and enter circulation, resulting in a variety of autoimmune diseases.
In the thymus, the AIRE causes transcription of a wide selection of organ-specific genes that create proteins that are usually only expressed in peripheral tissues, creating an "immunological self-shadow" in the thymus. It is important that self-reactive T cells that bind strongly to self-antigen are eliminated in the thymus (via the process of negative selection), otherwise they may later encounter and bind to their corresponding self-antigens and initiate an autoimmune reaction. Research in knockout mice has demonstrated that AIRE functions through initiating the transcription of a diverse set of self-antigens, such as insulin, in the thymus.

HLA Antigen-Presenting Pathway and Multiple Sclerosis

The HLA genes plays a crucial role in the development of Multiple Sclerosis (MS). The HLA genes are highly polymorphic, and the combination of alleles on a given chromosome is called a haplotype. The polymorphisms and MHC class II structure can impact peptide loading and presentation. In MS, the HLA-DRB11501 allele is the most strongly associated with the disease, and it is thought to present myelin-related antigens to T cells, leading to an autoimmune reaction against myelin. Other factors, such as allelic heterogeneity, gene-environment interactions, and epigenetics, may also contribute to the development of MS.

In summary, the immune system, with its innate and adaptive components, employs various pathways and mechanisms to protect the body. The intricate balance and regulation of these pathways are essential for effective immune response and prevention of autoimmune disorders. Understanding these mechanisms offers insights into potential therapeutic interventions for immune-related diseases.