Software modeling of the Complement System and its role in Immune Response Aparna Srikantaswamy,∗ Jugal Kalita,† Kaushal Chandrasekar,‡ Karen Newell§AND Patricia Giclas¶ [email protected], [email protected], [email protected], [email protected], AND [email protected] Abstract ment deficiencies and disease scenarios involving dif- ferent kinds of bacteria have been simulated using The complement system refers to a series of proteins this model. The performance of each pathway of ac- circulating in the blood that do the work of com- tivation is evaluated individually by running the sim- plementing antibodies in destroying bacteria. These ulation inputting only the required components and proteins circulate in an inactive form, but in response making the necessary changes. The software model to the recognition of the molecular components of the simulates thousands of biological entities consisting of pathogenic micro-organism, they become sequentially human cells, bacterial cells and complement system active, working in a manner wherein the activation components. A graphical depiction occurs simultane- and binding of one protein leads to the activation of ously on a small panel of the screen as the simulation the next protein in cascade resulting in the lysis of proceeds. A console output gets displayed indicating bacterial cells. There are three pathways of comple- the activated pathway, the complement system com- ment activation namely classical, lectin and alterna- ponents involved in it, the bacteria concentration on tive pathways. The initiation of complement cascade the terminal. The software written in C++ language in classical pathway is caused by formation of immune is a modification and enhancement of SIMISYS ver- complexes on the surface of the target cell. The alter- sion 0.3 [6], which models and simulates the basic native and lectin pathways are integral participants behavior of the human immune system. of non-specific innate immunity and hence do not re- quire any antibody involvement for activation. Using software, we have developed a model called SIMISYS version 0.4, which implements the activa- 1 The Immune system tion of the complement system by the three pathways and demonstrates the lysis of bacterial cells through Any immune response constitutes recognition of the the common membrane attack pathway. It gives the pathogen or other foreign material and the mounting statistics of the number of complement system com- of a reaction against it to eliminate it. An antigen ponents involved and the number of bacterial cells de- is recognized as foreign when epitopes of that anti- stroyed. The software model illustrates other benefi- gen bind to B cells and T cells by means of epitope- cial immune defense functions carried out by the com- specific receptor molecules whose shapes are comple- plement system components, namely chemotactic at- mentary to that of the epitope. Immune response can traction of phagocytes to the infection site, promotion be categorized either as innate immune response or of opsonization, triggering inflammation and removal adaptive immune response. The innate immune sys- of immune complexes from the circulation. Comple- tem is a less specific component of the immune system and forms the first line of defense against infection ∗Department of Computer Science, University of Colorado, from foreign micro-organism. Pathogen associated Colorado Springs, CO 80933 molecular patterns can also be recognized by a series †Department of Computer Science, University of Colorado, Colorado Springs, CO 80933 of soluble pattern recognition receptors in the blood ‡Department of Computer Science, University of Colorado, that function as opsonins and initiate the complement Colorado Springs, CO 80933 pathways. Some of the cells involved in an innate §Department of Biology, University of Colorado, Colorado immune response include neutrophils, macrophages, Springs, CO 80933 ¶National Jewish Medical and Research Center, 1400 Jack- mast cells, and basophils. Complement proteins and son Street, Denver, CO 80206 cytokines are some of the molecules involved. 1 The adaptive immune system is the more specific set of biochemical reactions ultimately attacking and component of the immune system and is capable lysing the target cells. This terminal process is called of specifically targeting and eliminating a foreign the membrane attack pathway or the lytic pathway, pathogen. It is capable of remembering the pathogen as it is responsible for lysis [5, 13, 15, 16]. The mem- and can build a fight against the intruder prevent- brane attack complex forms a large channel through ing it from causing disease later. Adaptive immune the membrane of the target cell, enabling ions and response improves by repeated exposure to a given small molecules to diffuse freely across the membrane infection and involves antigen presenting cells such [5, 15, 16]. as dendritic cells and macrophages, cytotoxic T cells, helper T cells and B cells and production of molecules like antibodies and cytokines [5]. However, the draw- 3 Implementation Overview back of the specificity of adaptive immune response is that only a few B cells and T cells in the body rec- The software model has been implemented using ob- ognize any one foreign epitope. These few cells then ject oriented C++ language on Red Hat Linux 9.0. It must rapidly multiply in order to produce enough has a multithreaded architecture based on pthreads cells to stage a defensive attack against that particu- [10]. The graphics are displayed using Simple Direct- lar epitope which usually takes several days. This du- Media Layer (SDL) version 1.2 [8]. An XML file has ration of time lets the pathogen to cause considerable been used to hold different types of complement com- harm and hence innate immunity is very essential as ponents, keeping in mind that the system will evolve the first line of defense [5]. over time. The Iksemel parser [1] has been used to parse this XML file. The resulting software model is able to simulate an effective defense mechanism 2 Complement System by the immune system with the aid of the comple- ment system against a bacterial attack. This model The complement system is part of the innate immune explores the different pathways of the complement system and forms the basis of antibody mediated system and is able to model disease scenarios. The immunity. Apart from defending against bacterial software model is integrated into SIMISYS version infection, it has other physiologic activities such as 0.3 [6] and is given the title SIMISYS version 0.4. It bridging innate and adaptive immunity, causing in- includes a graph, depicting the results of the simula- flammatory response and disposing offimmune com- tion being displayed on a small panel on the screen. plexes. Complement was first identified as a heat sen- A console output gets displayed simultaneously in- sitive principle found in the blood serum that comple- dicating the activated pathway, all the complement mented antibodies in destroying bacteria [5]. There system objects involved in it, the bacteria concen- are more than 30 complement proteins in the serum. tration, etc., on the terminal. The model allows the The ways in which the complement system is acti- user to be able to zoom in and zoom out using the vated are known as pathways. There are three path- respective keys on the keyboard. There are three dif- ways of activation namely classical, lectin and alter- ferent screens, each representing a different region of native pathways. The initiation of the complement the human body. These are the main screen repre- cascade in classical pathway is caused by the bind- senting the tissue, a second screen representing the ing of an antibody to an antigen on the surface of activities by the lymphnode object and a third screen the target cell. The alternative and lectin pathways displaying the activities carried out by the liver ob- provide non-specific innate immunity which does not ject. The T key on the keyboard enables one to toggle require any antibody [5, 13, 15, 16]. All the path- from one screen to another. Most operations carried ways of activation produce a key enzyme called C3 out in this modeling are string based operations. Pat- convertase. C3 convertase cleaves C3 into C3a and tern recognition through substring recognition and C3b [5, 13, 15, 16]. Normally the larger fragment is matching of the epitope or signature of each object is designated with a b attached to the component name the main idea used for movement, opsonization and and the smaller is designated with an a attached. immune complex clearance mechanisms. All of these three pathways essentially converge at The software model includes programs, which imple- a particular stage in the cascade and produce a com- ment the complement system as a vital part of the mon complex called C5 convertase which starts a new immune system. In this model, a three dimensional 2 Grid acts as a place holder for the biological enti- 0 0 1 1 \ ties and molecules. Each grid cell or position can Figure 1: Character array holding signature of C3b have a pointer to a biological entity like a human 1 1 0 0 cell or a bacterial cell and to a complement system \ object. Each complement system object references Figure 2: Character array holding CR1 receptor of the grid through a grid pointer and the grid keeps Erythrocyte entity track of complement system object present within its cells through a cs pointer. A grid pointer is used respective status to ACTIVE. The complementsystem by each entity to point to the grid position that it is object then appends a string representing the name situated in. Using the grid pointer, a cell can check of current type of component to the cellMembrane its neighboring grid positions for other entities, or attribute of the Bacteria object, which is also a inquire about the chemicals, and antibodies present string.