Host response to helmith infection Flashcards
Explain how a host responds to infection with helminths?
Which cell type are involved in detection of helmith infection and how do they work?
Epithelial cells are damaged due to the parasite, and secretes the alarmins (IL-25, IL-33, and TSLP) to stimulate the activation of ILC2 cells.
Innate lymphoid cells (ILCs) are important in amplifying immune responses; type 2 secretes the Th2-associated cytokines IL-4, IL-5 and IL-13 (hallmark cytokines), and the type 2 associated cytokines (IL-5, IL-9, and IL-13).
Th2 cells secretes the cytokines IL-4, IL-5, and IL-13 (hallmark cytokines), and can migrate from the infected tissue and back due to the “homing markers” via the blood.
DCs are activated when in contact with the parasite + the hallmark cytokines (especially IL-13). It results in a positive feedback loop of differentiated Th2 cells. After engulfed the free parasitic antigen (released by the parasite itself or after the parasite has been killed (necrosis)), it migrates to a draining lymph node via the lymphatics.
Follicular Th cells migrates to the LN and activates B cells. They are specific for the parasitic antigen or one particular peptide associated with one specific MHC molecule. They have chemokine receptors.
Innate lymphoid cells type 2 (ILC2) have an important role in the immune response to helminth infection. Describe their main function and how they become activated.
ILC2 main function is to secrete Th2 associated cytokines IL-4, IL-5, and IL13. They become activated by the epithelial secreted “alarmers” cytokines IL-25 and IL-33.
What roles do macrophages; mast cells; and granulocytes have in immune responses against helminths?
Mast cells are located at body surface; skin, body cavities, underneath the epithelium. They express high affinity Fc-epsilon receptors on its surface that bind tightly to the IgE antibody - function as a prolonged receptor on the cell surface which bind to the parasite. Degranulation occurs when at least 2 of the FcR+IgE binds to the parasite and are cross-linked. This activates the release of granule content (inflammatory immediate; ex: histamines). And, results in the activation of the endothelium of the local blood vessel to become penetrable for cells (eosinophils and dTh2 cells) and more plasma proteins (IgE). This is known as vascular leakage and causes a local inflammation (due to the production of inflammatory cytokines - ex: TNF-alpha - by the mast cells.
Eosinophils is a type of granulocytes (in addition to neutrophils and basophils) that migrate from the bone marrow. They must be activated by Th2 secreted IL-5 cytokines to activate the expression of the high affinity Fc-epsilon receptors. They are also involved in the degranulation to release inflammatory immediate.
Macrophages (type 2) are alternatively activated macrophages (AAMs), which do not secrete inflammatory cytokines but factors that stimulate tissue repair. They have an anti-parasitic effector function.
Describe an adaptive immune response to helminth infection, including activation of dendritic cells, T cells, and B cells. Also include the main cytokines, antibody isotype and the types of T cells that are typically involved in efficient anti-helminth immunity.
DCs: the type 2 DCs get activated via IL-13 when phagocytosing parasitic antigen, before migrating to a draining LN to start the adaptive immune response. In the LN; they are stimulating naive CD4+ T cells to become differentiated into Th2 cells (against intrinsic infections - ex: larvae). The peptide presentation via MHC-II molecules (mostly, but when there is an intrinsic infection by larvae the MHC-I are also presenting the peptide to the CD8+ T cells). Co-stimulations between CD4+ co-receptor and co-stimulatory molecules (B7 on DCs; CD28 on CD4+ T cells).
B cells: get stimulated by follicular Th cells that secrete cytokines IL-4 and IL-13. The B cells have specific receptors for free parasitic antigens migrating via the lymph to the B follicles in the LN. Activating receptor-mediated endocytosis and process it for antigen presentation to the follicular Th cells (effector T cell) for a secondary activation via cell-to-cell contact (CD40/CD40L). They also binds to the co-stimulator CD28, which enhances the immune response. The B cell will differentiate into either B memory cell or plasma cells that produce immunoglobins (in this case; especially IgE).
Describe two main functions of T cells in immune responses against helminths.
1: secrete the Th2-associated cytokines: IL-4, IL-5, and IL-13.
2: stimulate the B cells in the LN to produce IgE.
Describe the main functions of antibodies in immune responses against helminths. Which main cell types are involved (besides from plasma cells)?
The main function of antibodies (IgE) in response to worms are binding to the worm to recognize the presence of the parasite; migrate to a LN to stimulate the differentiation of B cells; bind to the mast cells and eosinophils Fc-epsilon receptors (high affinity) to enhance the binding affinity to the worm due to high sensitivity; trigger mast cell degranulation to induce vascular leakage and local inflammation and thus recruit more immune cells.
Discuss the role of regulatory cells and molecules in chronic helminth infection. Some parasites produce molecules that mimic host regulatory cytokines. How may this benefit the parasite?
The role of regulatory cells (Tregs) and molecules in chronic helmith infection involves: function as immunoregulators due to the FoxP3+ Tregs which produces TGF-beta (a regulatory cytokines that control both Th1 and Th2 cytokine levels and promotes the production of IL-10); interleukin 10 (IL-10) is important in the production of FoxP3+ Tregs, the induction of host protection against T. murins following acute infection, and the control of INF-gamma-mediated intestinal pathology following chronic infection, as well as anti-IL-10R antibody treatment during the chronic stages of infection led to an increase in FoxP3+ Tregs in the draining LN; eosinophilia which is seen in the infected hosts within any parasitic clearance.
The amount of parasites that benefit form producing molecules that mimic host regulatory cytokines are: H. polygyrus that produces TGF-beta mimic that induce the production of Tregs in vitro + IL-6 induced modification of the Treg population; and T muris which has IL-10 induction of host protection against acute infection.
Describe the role of the epithelium and mucus in the expulsion of GI helminths. How is mucus production stimulated in anti-helminth immune responses?
The mucus production of the goblet cells are stimulated by the Th2-associated cytokines IL-4 and IL-13. the cells produce different types of mucus (thicker and thinner) where the thicker is more effective against parasites.
What type of anti-helminth function does the expression “weep and sweep” refer to? Specifically, what is the “weep” and what is the “sweep”?
The type of anti-helmith function the expression of “weep and sweep” is referred to is the promotion of intestinal muscle contraction, as well as the enhancement of goblet cells and epithelial hyperplasia. It involves type 2 cytokines including IL-9
Weep = mucus production
Sweep = smooth muscle contraction
