The distinction between an antigen and a pathogen is subtle, but key to understanding the dynamic interplay and crosstalk of the innate and acquired immune system. A pathogen is a microbe that can make you sick and includes a vast array of opportunistic insults such as bacteria, viruses, protozoa and fungi that leads to an infection.(Payseur 2017) An antigen is a component of a pathogen (e.g., cell surface markers comprised of proteins, complex carbohydrates) that is identified by macrophages of the innate immune system as “foreign” to the body.
The macrophage engulfs and digests the foreign components and then displays components of the recognized foreign fragments on the cell surface of the macrophage (antigen-presenting macrophage), which then interacts with circulating T-helper cells of the acquired immune system to engage further immunoprotection through interleukin signaling forming cytotoxic T and B cells. When B cells become activated by T-helper cells, they differentiate into plasma cells which can rapidly form and circulate in the blood stream with antibodies that can bind to the antigens originally engaged by the macrophage.
However, some of the activated B-cells become memory B cells which enable a faster and more robust response to a subsequent exposure of the same pathogen. (O’Laughlin 2017) Understanding this bio-molecular recognition and activation process involving the innate and acquired immune system will ultimately lead to better and more effective approaches to enhance immune protection.(Sela-Culang, Kunik et al. 2013)
Streptococcus – A Bacterial Pathogen
An example of a common bacterial pathogen that causes strep throat is Streptococcus. The common cold, influenza and chicken pox are examples of infections caused by viruses. Protozoa and fungi can also cause devastating illness in susceptible individuals. Malaria, a life-threatening illness, is an example of an infection of red blood cells due to a single cell protozoan, delivered typically by infected mosquitoes. A common yeast infection is due to the infection and overgrowth of fungi called Candida albicans.(Payseur 2017)
Lyme Disease – A Tick-borne Bacterial Infection
Lyme disease is an infection by the bacteria Borrelia burgdorferi typically transmitted by the Ixodes tick, also referred to as deer ticks or black legged ticks. The ticks are typically found in wooded and grassy areas. Lyme disease is found throughout the United States and can be found in over 60 other countries.(Lymedisease.org 2017) The Centers for Disease Control (CDC) estimates that 300,000 people of all ages in the US are diagnosed with Lyme disease every year. However, the diagnosis of Lyme disease can be very difficult.(CDC 2015)
Lyme disease symptoms are highly diverse and appear to mimic many other possible illnesses. Typical symptoms of Lyme disease include, fever, headache, fatigue and characteristic rash called erythema migrans. (Wormser, Dattwyler et al. 2006; CDC 2015). Treatment is usually managed in the early stages with antibiotics (doxycycline, amoxicillin, cefuroxime axetil). However, if left untreated, the infection can spread to multiple tissues and organs including joints, the heart and the nervous system and require intravenous administration of antibiotics (ceftriaxone or penicillin). As the infection spreads, the ability to manage the symptoms and consequences becomes more complicated. An expert panel of the Infectious Diseases Society of America has developed guidelines for the clinical assessment, treatment and prevention of Lyme disease (Wormser, Dattwyler et al. 2006) The CDC has an excellent patient brochure that describes Lyme disease that clinicians may find helpful in supporting the needs of the patient. (CDC 2017)
Major Histocompatibility Complex (MHC) Proteins (Class I or Class II) Dictate the Subsequent Engagement of the Innate Immune System and Trigger Different Responses
There are two major classes of MHC proteins that interact with cells of the innate immune system. The two classes of MHC are MHC I and MHC II. In both classes of MHC, the proteins bind peptides which it can then present at the cell surface to a T cell to promote an immune response. MHC class I molecules present peptides to the surface of CD8+ cells, whereas MHC II present peptides to CD4+ cells. (Neefjes, Jongsma et al. 2011)T cells only recognize antigens as complexes with MHC molecules. It is important to recognize that MHC class I and MHC class II proteins are specialized to present different types of antigens, thereby eliciting different responses.
MHC class I glycoproteins are present on almost every cell in the body. Their role is to present endogenous or intracellular antigens that originate from cytoplasmic or nuclear origin via proteasome-mediated degradation of proteins that are at the end of their functional lives. The antigens for MHC class 1 are self-proteins and also foreign proteins produced within the cells, such as viral proteins that take over the cells machinery in order to replicate the virus. When the foreign protein is degraded, the peptide fragments are transported to the endoplasmic reticulum, where they can bind to MHC I proteins prior to transport to the cell surface via the Golgi apparatus of the cell. Once the peptide fragments from the foreign protein are localized to the cell surface, the membrane-bound MHC I protein displays the antigen for recognition by cytotoxic T cell lymphocytes. MHC I proteins bound with foreign protein on the cell surface are monitored by killer T cells as part of the surveillance system that identifies and destroys any cell with over-abundant or unfamiliar peptide antigens, such as malignant cells or those harboring viruses.
MHC class II glycoproteins are only present on specialized antigen-presenting immune cells, including macrophages that engulf foreign particles such as bacteria, dendritic cells that present antigen to T cells and B cells that produce antibodies. MHC II class proteins present exogenous antigens that originate extracellularly from foreign bodies such as bacteria. Upon encountering a pathogenic organism, proteins from the pathogen can be degraded into peptide fragments (phagocytosis) by the antigen presenting cell, which then sequesters these fragments into the endosome so they can then bind to MHC II proteins, before being transported to the cell surface. Once at the cell surface, the membrane-bound MHC II protein displays the antigen for recognition by a difference type of T cell, the helper T cell lymphocyte. The T helper cells are activated upon binding to macrophage or dendritic cell MHC II antigen causing the release of lymphokines that attract other cells to the infected area in an attempt to confine and destroy the antigenic material. Additionally, the binding of T helper cells to B cell MHC II antigen stimulates the development of a clone of antibody-producing cells against the antigenic material.(InterPro.2017)
A Dysfunctional MHC HLA Complex May Predispose Individuals to Autoimmune Disease
The ligand for the activated T-helper cell receptor is a major histocompatibility complex (MHC), which is a complex of genes coding for a family of proteins, many of which function in the immune system. In particular, HLA-DR (Human Leukocyte Antigen-antigen D Related) is an MHC class II cell surface receptor encoded by the human leukocyte antigen complex on chromosome 6. The complex of HLA-DR and its ligand (a peptide of 9 amino acids in length or longer) constitutes a ligand for the CD4+T helper cell receptor. The primary function of HLA-DR is to present peptide antigens, potentially foreign in origin, to the immune system for the purpose of eliciting or suppressing T-helper cell responses that lead to the production of antibodies against the same peptide antigen. Antigen presenting cells (macrophages, B-cells and dendritic cells are the cells in which DR are typically found. Increased abundance of the DR antigen on the cell surface is often in response to stimulation. The HLA DR protein can be assayed as a marker for immune stimulation.(Stokkers, Reitsma et al. 1999)
Researchers have reported a strong association between the HLA class II encoded HLA-DRB (beta chain, which is the most prevalent beta subunit of HLA-DR) and several autoimmune diseases including rheumatoid arthritis, type 1 diabetes, Graves’ disease, ulcerative colitis and Crohn’s disease.(Tiwari and Terasaki 1981; Stokkers, Reitsma et al. 1999; Gough and Simmonds 2007) Tomasi et al., reported that MHC class II regulation by epigenetic agents and microRNAs.(Tomasi, Magner et al. 2010) An unexpected finding was that Dicer expression (an enzyme of the RNase III endoribonuclease family required for the production of miRNA) (Devasthanam and Tomasi 2014) is altered by treatments with several agents such as interferons and cortisone, typically employed in the treatment of immune disorders. HLA antibodies can cause acute and chronic antibody mediated rejection and decreased graft survival, despite good matches allografts and solid organ transplantation.(Butler, Valenzuela et al. 2017) Collectively, the research suggests that alterations in the MHC HLA Complex due to epigenetic factors may lead to autoimmune reactions that lead to chronic inflammation and chronic disease.