When acute inflammation is not sufficient to deal with a pathogen, chronic inflammation takes over. Chronic inflammation is mediated by B-Cell and T-Cell leukocytes/lymphocytes. These white blood cells make up the Adaptive Immune System which takes longer to kick in than innate immunity, but has higher potency and specificity.

B-Cells are the leukocytes that turn into plasma cells and release antibody once they have been activated. Antibody is the most important part of the Humoral Immune system. It is a secreted free floating form of the B-Cell Receptor. So whatever antigen activated the B-Cell through an interaction with the BCR will also be recognized by the antibody. Antibody will be discussed in much greater detail in our next section. B Cells are activated primarily in response to extracellular pathogens (mostly bacteria).

There are 2 main types of T-Cell, each of which is part of Cell-Mediated Immunity. CD8 T-cells, named for its CD8 surface marker, are the “Cytotoxic” T-Cell. These lymphocytes release perforin and granzyme to cause lysis of infected cells, similar to how NK cells function. These CD8 cells cause apoptosis of cells that are infected by intracellular pathogens (primarily viruses and intracellular bacteria like chlamydia). Cytotoxic T-Cells also play a role in triggering apoptosis of cancerous cells. CD4 T-Cells, named for their CD4 surface marker, are referred to as the “Helper” T-cells. They do not fight pathogens directly, but help various other cells to do so by releasing cytokines signals. There are 2 subtypes of CD4 Helper T-Cells, Th1 and Th2. Th1 Helper T-Cells primarily activate cytotoxic CD8 T-cells and Macrophages. Th2 helper T-cells primarily activate B-Cells.

Both T-Cells & B-Cells begin life in the bone marrow and arise from multipotent hematopoietic stem cells. Immature B-Cells remain in the bone marrow to complete maturation (Think B for Bone Marrow), while the immature T-Cells leave the bone marrow and travel to the thymus to complete maturation (Think T for Thymus). The bone marrow and thymus are referred to as Primary Lymphoid Organs. These Primary Lymphoid Organs are where B-Cells and T-Cells differentiate and mature. Absence of a primary lymphoid organ, such as the absence of the thymus in DiGeorge Syndrome, prevents the normal development of white blood cells and can lead to immunodeficiency.

Once mature, B-Cells and T-Cells move to Secondary Lymphoid Organs such as the lymph node and spleen. This is where these cells come into contact with foreign pathogens. If the pathogen the cell can interact with is present the cell will be activated. After activation the cells proliferate making clones of themselves that are all capable of recognizing and fighting against the same antigen. However, not all T & B Cells will be activated. A large majority of these cells will not encounter the type of foreign material they recognize. If the foreign material the B or T Cell can fight against isn’t present in the body there is no need to be activated.

The foreign material or pathogen that the T & B Cells recognize is determined by their unique surface receptors. An Antigen is the specific structural sequence the receptor can bind to. For example, a protein fragment of a pathogen you want to mount an immune response against. All of the receptors on a given T or B Cell are the same and recognize the same antigen. When the receptor binds to the appropriate antigen it signals the cell to become activated and proliferate. You need a nearly infinite variability in these receptors so that you can fight almost any pathogen encountered. Therefore, while the leukocytes are in the primary lymphoid organs a wide variety of receptor variability is randomly generated through VDJ Recombination. This change in the portion of the genome that encodes for the cell’s receptors allows the different leukocytes to interact with a huge variety of antigens.

The problem with randomly generating surface receptors is that some of these leukocytes will now be able to bind the body’s own cells. If these self-reactive lymphocytes where activated they would cause autoimmune damage where the immune system targets the body’s tissue instead of foreign material. The body has a 2 step process for preventing this called Negative Selection. In the primary lymphoid organs self-reactive leukocytes are removed by Central Tolerance (AKA Clonal Deletion). Developing T & B lymphocytes that interact too strongly with self-antigens undergo apoptosis or programmed cell death. In the secondary lymphoid organs there is a similar process called Peripheral Tolerance or Clonal Anergy. Here self-reactive T or B Cells that bind to soluble self-antigens undergo anergy. Anergy is when a cell is prevented from becoming active. These anergic cells are not killed, but they are prevented from proliferating.

Major Histocompatibility Complexes (MHCs) are cell surface molecules encoded by the Human Leukocyte Antigen (HLA) genes. MHCs present antigens to T-Cell receptors. TCRs cannot recognize an antigen unless it is presented by the MHC. When the TCR binds to the correct antigen-MHC complex the T-Cell is activated. For the purposes of the Step 1 exam there are two main types of MHC, MHC I and MHC II. MHC I is present on all nucleated cells (basically every cell other than red blood cells) and activates CD8 T-cells. MHC II is present primarily on antigen presenting cells and activates CD4 T-cells. The best way to remember this is a simple math mnemonic.

CD4 T-Cells are activated by an interaction with Antigen Presenting Cells (APCs). These APCs (usually macrophages and dendritic cells) phagocytose extracellular pathogens, break them up into fragments, and then present those fragments on their surface MHC II for CD4 T-cells to recognize. To prevent accidental activation, there are multiple points of control in this interaction and all of them must be present to activate the CD4 T-cell. First the TCR must recognize the antigen it has specificity for while also recognizing that the antigen is being presented on an MHC molecule. An antigen independent signal called the costimulatory signal is required as well. Here CD28 surface molecules on the T-Cell recognize B7 surface molecules on the APC. CD8 T-cells are activated by an interaction with a cell that has an intracellular infection. This infected cell can be of almost any type. The antigen is “presented” on the surface MHC I of the infected cell. To become active the CD8 cell must recognize the antigen and MHC. CD8 cells also require the same co-stimulatory signal as CD4 cells (B7 binding to CD28).

With CD4 & CD8 cells the antigen presented must be a protein (AKA peptide). Other macromolecules like carbohydrates can illicit an immune response via other mechanisms, but the response is much greater to a protein antigen because T-Cells are involved. This is why vaccines that contain a carbohydrate capsular antigen often conjugate the antigen to a peptide.

There are two ways B-Cells can be activated, T-Cell Independent & T-Cell Dependent Activation. During T-Cell Dependent B-Cell Activation an interaction with Th2 Helper T-Cells is required. Here an inactive B-Cell phagocytoses an extracellular pathogen and acts as the antigen presenting cell by presenting a fragment of the pathogen (AKA the antigen the B-Cell Receptor recognizes) on its MHC II to the inactive T-Cell. This leads to activation of the T-Cell which then releases cytokines to activate the B-Cell.

In T-Cell Independent B-Cell Activation free floating antigen binds directly to the antibodies (B-Cell Receptor) on the surface of the B-cell. This type of B-Cell activation is less potent and does not result in isotype switching. This means that only IgM is created against the antigen.

Cytokines are small proteins used as signaling molecules during immune response and inflammation

• Interleukin 1 (IL-1) is released by sentinel macrophages during acute inflammation to cause a change in the vessel endothelium that promotes neutrophil extravasion. It also plays a role in the formation of fever.
• Interleukin 2 (IL-2) is secreted by T-Cells to stimulate the proliferations of other T-Cells during an immune response. Some immunosuppressants inhibit IL-2 function in order to decrease the immune response. IL-2 also activates NK Cells and recombinant IL-2 can be given to increase their activity to fight certain cancers.
• Interleukin-8 (IL-8) and Leukotriene B4 (LTB4) are chemotactic factors which attract neutrophils along with C5a during acute inflammation.
• Interferon (IFN) is released by T cells and NK Cells in response to intracellular infections like TB or viruses. IFN activates macrophage phagocytic activity and causes infected cells to inhibit virus protein synthesis. IFN also plays a key role in activating macrophages to form granulomas.
• Tumor Necrosis Factor (TNF) mediates septic shock as well as increasing apoptosis of cancer cells (hence its name). TNF also acts similarly to IL-1 during neutrophil recruitment. Inhibitors of TNF can be used to treat things like rheumatoid arthritis.