Monday, November 14, 2011

Immunology II: Lymphoid Organs and Cells

As mentioned in the last post, several types of cells derive from lymphoid progenitor cells.  These cells are generated in the bone marrow in general, but only B cells mature there (hence the name B cells).  In contrast, T cells migrate to the thymus where they mature.  After full maturation of both B and T cells, they circulate in the blood system and then enter the peripheral lymphoid organs.  The central lymphoid organs are the bone marrow where the lymphocytes are generated, whereas the peripheral lymphoid organs are where T cells mature and where the adaptive immune responds to various stimuli.

The peripheral lymphoid organs
First, we will consider the components of the peripheral lymphoid system.  The lymph nodes are glands right near each armpit that is where fluid collects from the lymph system.  Lymph drains into the lymph nodes via lymphatic vessels and consists of the extracellular fluid filtered from the blood.  Thus, lymph is kind of a surveillance system for the body.  The afferent lymphatic vessels carry lymph and cells from infected tissues and drain into the lymph node.

The lymph node itself has a unique structure, illustrated to the right.  The follicles are where B lymphocytes set up shop, and T cells exist in paracortical areas (T-cell zones).  Germinal centers within the lymph node are where B cells proliferate after they have been stimulated by T cells.  Several additional tissues are organized similar to the lymph node drawn to the right, and this structure facilitates interaction between B and T cells.

The spleen is another peripheral lymphoid organ that mostly works to break down dead red blood cells.  This destruction occurs in the red pulp of the spleen, but the spleen also has white pulp where lymphocytes enter and exist within the spleen.  Within the white pulp is the periarteriolar lymphoid sheath (PALS) that contains T cells and a B-cell corona.

The digestive system is a major route for infection and has several gut-associated lymphoid tissues (GALT).  Some of these tissues include the tonsils, adenoids, and the appendix.  The intestine also has its own GALT, namely the Peyer's patches, which collect antigen directly from inside the intestine using multi-fenestrated (M) cells.

Similar to the digestive tract, the respiratory tract has its own lymphoid tissue, called the bronchial-associated lymphoid tissue (BALT).

Wednesday, November 9, 2011

The basics of immunology

Immunology scares me. I'm not ashamed to admit this fact. I find the topic intimidating and overwhelming, especially when I listen to talks given by prominent immunologists. The terminology is difficult, and the concepts seem very intertwined. I've always perceived that breaking into understanding immunology required a lot of work but that it would (and should) make sense... eventually.

 The next few blog posts are going to focus on immunology, not only because I need to learn this information, but also because it is fascinating and a challenging topic.

Components of the Immune System
All of the cells that comprise the immune system emerge from the bone marrow, where all of them originally come from and where some of them remain for maturation.  The cell type that gives rise to immune cells is the hematopoietic stem cell.  From this pluripotent state, the hematopoetic stem cell can then mature into a myeloid progenitor cell or a common lymphoid progenitor.  Myeloid progenitor cells can differentiate into several more cell types, including granulocyte and macrophage progenitors and megakaryocyte and erythrocyte progenitors.  The granulocyte and macrophage progenitors can then develop into neutrophils, eosinophils, basophils, mast cells, and macrophages.  Megakaryocyte and erythrocyte progenitors generate platelets upon maturation.

Hematopoietic stem cells can also develop into a common lymphoid progenitor, which consists of B cells, T cells, and NK cells.  These types of cells leave the bone marrow and migrate through the lymph nodes.  Dendritic cells also develop from lymphoid progenitor cells but mature in the bone marrow before entering the lymph node.

Basic functions of immune cells
  • Macrophages are a common cell type that mature from monocytes (from the myeloid progenitor cells originally).  Monocytes circulate in the blood and continuously differentiate into macrophages when they enter the body's tissues.  Once in the tissues, macrophages can be considered the garge trucks of the body:  they engulf the environment as well as other cells in the process of phagocytosis.  Thus, macrophages can function to neutralize harmful elements within the body.
  • Dendritic cells also mature from myeloid progenitor cells, and their main function is to process and display antigen that will then be readable by T lymphocytes.  This antigen display requires the presentation of co-stimulatory molecules, and when dendritic cells encounter a pathogen (or other foreign antigen), they mature and begin expressing these co-stimulatory molecules.
  • Mast cells differentiate in body tissues and are involved in mediating mucosal immunity.  They are most well-known for their role in allergic reactions.
  • Neutrophils are a type of granulocyte (so called because they have densely-staining and strange-shaped nuclei) that are involved in phagocytosis and increase in numbers upon an immune response.
  • Eosinophils respond to parasites.
  • Basophils may function similarly to mast cells.
  • B cells differentiate into plasma cells and function to secrete antibodies.
  • T cells destroy virus-infected cells and also function to activate other immune cells, such as B cells and macrophages.
  • NK cells are involved in innate immunity and destroy "weird-looking" cells, such as tumor cells or cells infected with viruses.
References for the interested:
Immunobiology. Janeway, Travers, Walport, Shlomchik.
Basic Concepts of Immunology and Neuroimmunology: Basic Immunology

Wednesday, November 2, 2011

Cancer and Oncogenes

Cancer is a diverse group of diseases with one common characteristic: unchecked cellular replication.  Via several potential mechanisms, cancer cells are able to avoid all of the checkpoints involved in cell growth and division, thus enabling them to divide more frequently or indefinitely.  Many events can lead to the development of a cancer cell, including inheritance of mutated DNA or the activity of a carcinogen, or a chemical agent that leads to the development of cancer.

Gene expression is often deregulated in cancer cells such that some genes are overexpressed, while others are underexpressed.  Genes that can be mutated to lead to an upregulation of activity and lead to the development of a cancer cell are termed proto-oncogenes.  When these proto-oncogenes are actually mutated, they are considered oncogenes.

An oncogene is often a gene involved in regulating cell division and drive the cell cycle.  When they are overexpressed, such as during cancer, they can push the cell to divide more frequently and, with further mutations, transform the cell such that it divides without restriction.

Oncogenes were first discovered in viruses, specifically in Rous Sarcoma Virus (RSV), a retrovirus that encodes a homologue to cellular src kinase (the viral form called v-src).  Tumors in birds caused by RSV are the result of v-src causing unregulated cellular proliferation.  Large amounts of research into this area has identified cellular src kinase as a proto-oncogene that, when mutated to become constitutively active, becomes an oncogene and can drive cancer development.  Interestingly, viruses have highlighted a number of cellular oncogenes and pathways that are improperly regulated in cancer.  Over 20 viral oncogenes have been identified to date.

Cellular proto-oncogenes (the genes before they become oncogenes) can promote cellular proliferation and the development of cancer in several ways.  One of these ways is to be overexpressed and function when the gene product really shouldn't function.  This is the case with proteins such as myc and growth factor receptors.  With overexpression of these proteins, there is the potential for amplified signaling through these pathways that can push the cell to divide more than it normally does, leading to the development of cancer.  An additional mechanism whereby a proto-oncogene can become an oncogene is via mutation that leads to improper regulation, such as constitutive activity.  A classical example of this type of phenomenon is via Ras, which when mutated is constitutively active and cannot hydrolyze an attached GTP to inactivate.  Thus, Ras remains active and cannot be "turned off."  This constant activity of Ras results in  signal transduction to the nucleus of the cell and pushes the cell to divide through transcription of several genes involved in cell division.

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