Week 1 - Wednesday Flashcards
Where is the spleen located?
The spleen resides in the left upper quadrant, retroperitoneal, along ribs 9, 10 and 11.
An immunoglobulin is isolated and identified. It is found at low levels in serum, but plays a major role in fighting helminthic infections. What is the likely class of this immunoglobulin?
IgE:
Before binding to antigen, IgE binds tightly to Fc receptors on basophils and mast cells — thus, it is the least common Ig in serum.
Once bound to the Fc receptors on basophils and mast cells, binding of cognate antigen (e.g., allergens) by IgE triggers release of cytokines and other mediators involved in the allergic response — this is a Type 1HSR (hypersensitivity reaction).
During an infection with invasive helminths (e.g., Strongyloides, Trichinella, Ascaris, Necator, Ancylostoma), IgE mediates an ADCC (antibody-dependent cell-mediated cytotoxicity) response:
IgE binds to the surface of the helminth → eosinophils (which have Fc receptors for IgE, aka FcεRs) bind to the free Fc “tail” of the IgE, triggering eosinophil degranulation → release of cytotoxic mediators (e.g., lytic enzymes, perforin, granzymes, tumor necrosis factor) to try to kill the helminth.
Serum levels of IgE tend to rise during infections with invasive helminths (e.g., Strongyloides, Trichinella, Ascaris, Necator, Ancylostoma).
What is the pathway blood travels through in the spleen?
Blood is filtered through the spleen via the following route: splenic artery → trabecular arteries → central arteries (surrounded by white pulp) → sinusoids (in red pulp) → red pulp veins → trabecular veins → splenic vein (notice how blood flows from inside the spleen towards the capsule, i.e. white pulp to red pulp)
With respect to immunology, define the term: “mature naïve lymphocytes”.
Definition:
“Mature naïve lymphocytes” = immunocompetent B- and T-cells which have already completed the selection process in the bone marrow and thymus, respectively, but have not yet been stimulated by foreign antigen.
“Mature” = immunocompetent = capable of mounting an immune response following antigenic stimulation
“Naïve” = not yet exposed to cognate antigen
What is the arterial supply of the spleen? What makes this unusual?
The spleen is derived, around the 6th week of development, from mesenchymal cells of the dorsal mesentery. Despite its mesenchymal origin, the spleen still shares blood supply with organs of the foregut. Specifically, the spleen receives blood from the splenic artery, the largest branch of the celiac trunk.
A posterior perforation of the stomach, typically due to an ulcer, may lead to perforation of the splenic artery.
What type of immunity does the complement system represent?
Innate immunity: includes many cellular and humoral devices, from nonspecific barriers (e.g., skin) to recognition and destruction of specific pathogens (e.g., complement-mediated opsonization of microorganisms for subsequent phagocytosis).
Innate immunity is maintained by a vast repertoire of serum proteins that recognize general classes of invading agents and which constantly sample the local environment. This provides for a fast immune response; however the proteins do not exhibit any memory in the case of recurrent infection.
The innate immune system involves:
- NK (natural killer) cells
- Phagocytes, neutrophils
- Dendritic cells
- Complement
An ambitious college student is studying T-cell activation. On the topic of lymphocyte activation, which of the following is incorrectly paired?
AMHC-II and TCR
BB20 and CD 28
CMHC-I and TCR
DAPC and T helper cell
EB7 and CD 28
BB20 and CD 28
The first signal in T helper cell activation is foreign antigen presented on the MHC-II on the APC and recognized by the TCR of the T helper cell. The second signal is a costimulatory signal involving interaction of B7 from the APC-antigen presenting cell with CD28 on the T helper cell. Activation of the cytotoxic T cell involves the first signal, which involves endogenously synthesized (viral or self) proteins that are presented on MHC-I of the virus infected cell and recognized by TCR on the T cytotoxic cell. B20 is an associated marker on B cells and is not directly involved with T cell activation.
Cytotoxic (CD8+) T cell activation:
First signal: Antigen presentation via MHC-I of a virus-infected cell. This is recognized by TCR on the cytotoxic T cell. The CD8 co-receptor stabilizes this interaction.
Second signal: IL-2 secreted by Th cells binds IL-2R on CD8+ cells → activation to kill the virus infected cell.
What are the two major components of the white pulp?
The white pulp is a major center for production and development of lymphocytes. Within the white pulp, exists the periarteriolar lymphatic sheath (PALS) and lymphoid nodules called Malpighian corpuscles (not to be confused with Malpighian renal corpuscles).
The periarterial lymphatic sheath (PALS) surrounds the central arteriole in the white pulp and is composed of T cells. Dendritic cells may also be found in the PALS area, functioning as APCs for their neighboring T cells.
The lymphoid nodules contain germinal centers, which are primarily composed of B cells.
What cells are B cells derived from? What type of B cell is released into the circulation from the bone marrow?
Lymphoid stem cell → pro-B cell (progenitor) → pre-B cell (cytoplasmic μ) → immature B cell (surface IgM), which is released into the circulation and is called a mature (naïve) B cell when it simultaneously expresses both surface IgM+ and IgD+ (via alternative splicing).
Can you describe 3 general steps involved in the T cell-dependent activation of a naïve B cell?
T cell-dependent activation of a mature (naïve) B cell (surface IgM+ and IgD+) involves 3 steps:
1) B cell surface immunoglobulins (B cell receptors) are bound and cross-linked by their specific cognate antigen → clustering of B cell receptors triggers endocytosis of receptor-antigen complexes into the B cell cytoplasm
2) Endocytosed antigen is dissociated from the B-cell receptor and then cross-linked toMHC class II peptides → antigen-MHC II complexes are then inserted into the B cell membrane and displayed on the B cell surface 3) TH (Helper T cells) recognize this MHC-complexed antigen and provide a co-stimulatory signal.
The co-stimulatory signal is required for activation of B cells and differentiation into plasma cells.
- B7 protein on B cell interacts with CD28 on Th cell → activates Th cell
- CD40 protein on B cell interacts with CD40L (CD40 ligand) on Th cell → activates B cell.
Describe the paracortex of a typical lymph node.
Paracortex: T-cell rich area that lies between the lymph node cortex and medulla.
Paracortex = site where antigen is presented (by APCs) to T helper cells and some B cells → stimulated B and T cells travel to the cortex to activate the primary follicles, forming secondary follicles with germinal centers
Paracortical size / cellularity varies depending on underlying pathology — for example:
- In immunocompetent patients, certain types of infections stimulate lymphocyte proliferation → ↑ number of circulating lymphocytes → hyperplastic, larger-than-normalparacortex due to massive lymphocyte influx
- Thymic aplasia or hypoplasia (e.g., DiGeorge syndrome) → ↓ number of circulating lymphocytes → hypoplastic, smaller-than-normal paracortex due to lack of lymphocyte influx
What is a role of the spleen during fetal development that is usually pathogenic in an adult?
During development, the spleen is responsible for fetal erythropoiesis between the second to seventh months (the liver and bone marrow are also partially responsible for hematopoiesis during this time as well). Splenic erythropoiesis after birth is usually pathogenic.
What are secondary lymphoid organs? Do they facilitate a process that is antigen-dependent or antigen-independent?
Secondary lymphoid organs: sites of antigenic stimulation of mature naïve lymphocytes → lymphocyte activation. This process is clearly antigen-dependent (i.e., stimulation byforeign antigen is required).
Normally, all secondary lymphoid organs have lymphoid follicles.
Secondary lymphoid organs include:
- Lymph nodes
- Spleen
- MALT (mucosal-associated lymphoid tissue) — e.g., tonsils, adenoid glands, Peyer’s patches
Where does positive and negative selection of T-cells occur in the thymus?
The Thymus is the major site of T-Cell development
Functions to convert hematopoietic progenitor cells → immature thymocytes → T-cells
The entire organ is enclosed by an investing capsule. Just deep to the capsule is the cortex. The medulla is the thymic center.
Formed by fusion of the ventral wings of the third branchial pouch
Cortex: dense with immature T-cells. It is the predominant site of positive selection (selecting functional T-cells).
Medulla: pale-colored because it contains mature T-cells, epithelial reticular cells, andHassall’s corpuscles (remains of epithelial tubes which grow out from the third branchial pouches).
It is the predominant site of negative selection (elimination of autoreactive T cells).
Positive selection induces apoptosis of cells that bind too weakly while negative selection induces apoptosis of cells that bind too strongly. Cells with high-medium binding survive. Binding refers to the ability of the T-cell receptors to bind to either MHCclass I/II or peptide molecules.
What are the two major functions of the spleen (in general)?
The spleen is a secondary lymphoid organ with roles in blood filtration and microbial defense.
Describe the medulla of a typical lymph node.
Medulla: consists of large blood vessels, medullary cords, and medullary sinuses
Medullary cords are rich with antibody-producing plasma cells
These antibodies exit the lymph node via cortical sinuses, which drain into the medullary sinuses, then into the efferent lymphatics
Medullary sinuses are endothelial-lined lymphatic spaces that collect lymph destined for the efferent lymphatics. They contain macrophages and reticular cells.
Describe the medulla of a typical lymph node.
Medulla: consists of large blood vessels, medullary cords, and medullary sinuses
Medullary cords are rich with antibody-producing plasma cells
These antibodies exit the lymph node via cortical sinuses, which drain into the medullary sinuses, then into the efferent lymphatics
Medullary sinuses are endothelial-lined lymphatic spaces that collect lymph destined for the efferent lymphatics. They contain macrophages and reticular cells.
Each B cell can only make Ig (immunoglobulin) specific to one antigen — what determines each B cell’s idiotype?
Each B cell’s antigen specificity (idiotype) is determined by the three-dimensional shape formed by the N-terminal of heavy and light chains (at the tips of the “Y”).
B cells that are reactive to self antigens undergo clonal deletion in the bone marrow or are inactivated in the periphery (clonal anergy).
Through what specialized type of venules do lymphocytes enter lymph nodes?
HEVs (high endothelial (postcapillary) venules) transport T- and B-cells from the bloodstream to the lymph node paracortex:
In the bloodstream, L-selectins on mature naïve lymphocytes weakly bind to addressins on endothelium →
This weak interaction allows stronger integrin-mediated binding and subsequent diapedesis →
Lymphocytes leave the blood and are carried by HEVs into the paracortical area of lymph nodes.
Guided by chemokine gradients, B-cells migrate to the cortex while T cells primarily remain local within the paracortex.
What are the two main components of the red pulp of the spleen?
The red pulp is composed of the splenic cords of billroth and splenic (venous) sinusoids. The splenic sinuses are engorged with blood, giving this area its red color.
Sinusoids are marked by gaps in the endothelium that assist in the filtration of blood. Abnormal and/or aged red blood cells become trapped as they attempt to squeeze through the narrow spaces of the sinusoids. The trapped cells are subsequently removed by splenic macrophages.
Macrophages lining the splenic cords of billroth in the red pulp sample sinusoidal blood by extending processes through gaps in the sinusoidal endothelium and basement membrane. Here, they function to remove old and damaged red blood cells as well as encapsulated bacteria (recall SHiNE SKiS mnemonic for encapsulated bacteria – S. pneumonia, H. influenza type B, N. meningitides, E. coli, Salmonella, K. pneumonia, Group B Strep).
After a splenectomy, there is a significant risk for infection with encapsulated bacteria. Oftentimes patients will be prophylactically treated with antibiotics to prevent such infection. In addition, the following can be observed on a blood smear:
Howell-Jolly bodies in RBCs
Target cells
Thrombocytosis
Name 2 main functions of lymph nodes.
Lymph nodes are secondary lymphoid organs that perform 2 main functions:
- Nonspecific filtration of lymph — macrophages within lymph nodes may trap / destroy malignant cells, microorganisms (e.g., viruses, bacteria, fungi), debris (e.g., anthracotic pigment).
- Facilitates interaction between lymphocytes and APCs (antigen presenting cells —e.g., macrophages, dendritic cells) → activation of lymphocytes (e.g., B cells, T cells)
Where do all T cells originate from?
All T cells originate from hematopoietic stem cells in the bone marrow, however development takes place in the thymus.
The earliest thymocytes found in the thymus are CD4-CD8- → then CD4CD8 → thymocytes finally develop into either:
- CD4CD8-, also known simply as CD4 helper T cells, or Th cells; or
- CD4-CD8, also known simply as CD8 cytotoxic T cells, or CTLs.
Note: only 1-2 percent of T cells leave the thymus; most of the remaining T cells undergoapoptosis.
What is the function of the marginal zone of the spleen?
Between the white pulp and the red pulp is a marginal zone composed of antigen presenting cells (APCs) and specialized B cells. The primary role of the marginal zone is to trap antigens from circulation to present them to splenic lymphocytes.
An experimenter adds papain to a sample of IgG. Explain what would happen to an individual immunoglobulin and what the products of the reaction would be.
Papain is a proteolytic enzyme often used in experiments. It cleaves the peptide bonds at the hinge region of the antibody → 2 identical Fab fragments (which can bind antigen) and 1 Fc fragment (which can bind complement).