Physiology, Active Immunity


Article Author:
Hailey Grubbs


Article Editor:
Chadi Kahwaji


Editors In Chief:
Timothy Craig
Yoon Kim
Robert Hostoffer


Managing Editors:
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Scott Dulebohn
Sobhan Daneshfar
William Gossman
Pritesh Sheth
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Richard Ciresi
Hajira Basit
Phillip Hynes


Updated:
10/27/2018 12:31:20 PM

Introduction

The body’s immune system is crucial in preventing invasion and harm from a variety of microbiological organisms such as bacteria, viruses, fungi, and parasites. Many levels of protection are involved in this process. Physical barriers such as skin, mucous membranes, and the acidic environment of the gastrointestinal (GI) tract provide an initial defense. If these fail, the innate or non-specific immune system is next to respond. Innate immunity involves the release of cytokines, complement, and chemokines as well as neutrophils and macrophages to destroy the invading pathogens. When this is not enough, an antigen-specific or adaptive immune response is initiated, and antibodies, B cells, and T cells enter the battle. The generation of a specific response to an antigen is referred to as active immunity. Active immunity plays an important role in immune responses in the event of re-exposure and our utilization of vaccines.

Issues of Concern

The immune response may operate unregulated, overstimulated, or uncontrolled. This can lead to auto-immune diseases where the immune system targets self-proteins. Alternatively, the immune system can be poorly responsive or unresponsive to infection and disease leading to immunodeficiencies.

Cellular

Relevant Terms and Definitions

  • Immunogen: Protein or carbohydrate that is recognized and sufficiently activates an immune response
  • Antigen: A molecule that is recognized by a specific antibody or T-cell receptor (TCR)
  • Adjuvant: Prolongs the presence of antigen in tissue and enhances the immune response to an antigen; used in acquired or artificial immunization (vaccinations)
  • Dendritic cells (antigen presenting cells): Facilitate activation of an antigen-specific response by the innate system; presents antigens via major histone complexes to activate CD8 and CD4 T cells  
  • CD4 helper T cells: Facilitate cell-to-cell interactions and cytokine release to activate and control immune and inflammatory responses
  • CD8 cytotoxic T cells: Travel throughout the body looking for antigens presented by the MHC I molecules present on all nucleated cells. Activated by TH1-cell cytokine release of IL-2; destroy virally infected cells
  • Major histocompatibility complex (MHC) I: Found on all nucleated cells, play a significant role in determining “self.” Responsible for presenting intracellular antigens to CD8 T cells
  • MHC II: Found on antigen-presenting cells that interact with CD4 T cells; responsible for presenting exogenous antigens 
  • TH0: The initial role of activated CD4 T cells, promotes cell immunity by activating dendritic cells and stimulating lymphocyte growth; releases cytokines IL-2, IL-4, and IFN-gamma; can develop into TH1, TH2, TH17, or other TH cells
  • TH1: The response stimulated by the release of IL-12 from dendritic cells and macrophages; secretes IL-2, IFN-gamma, and TNF-beta; inhibited by IL-4 and IL-10; provides defense against intracellular infections and fungi
  • TH17: The early response to bacterial and fungal infections when IL-23 is released instead of IL-12. Releases IL-17, TNF-alpha, and chemokines 
  • TH2: The response that occurs in the absence of IL-12 and IFN-gamma; promotes systemic antibody driven response; releases IL-4, IL-5, IL-6, IL-10 cytokines
  • Plasma cells: Permanently differentiated B-cells that secrete antibodies 
  • Memory B cells: Long-lasting B-cells that are responsive to one particular antigen and become activated with re-exposure to the same antigen

Development

The adaptive (active) immune response takes 1 to 2 weeks to reach its full functioning capacity, much longer compared to the twelve hours required to activate the innate immunity completely. With the development of the adaptive immune response, comes a phenomenon called immunologic memory, an immune defense that can last a lifetime to provide a future defense if re-exposed to the same antigen.

Active immunity can be achieved naturally or acquired through vaccines. An example of this is a child who becomes ill with the chickenpox or varicella-zoster infection. During this illness, the child’s immune system will mount a specific response to the virus, and the child will have immunity moving forward. This is a natural, active immune response. An example of acquired immunity against varicella is through vaccination with the live attenuated varicella vaccine. With this method, the individual has never truly been infected by the organism. [1]

Organ Systems Involved

The thymus serves as a site for T-cell development. Epithelial cells in the thymus have a unique ability to express most proteins in the human genome which allows for screening and destruction of self-reactive T cells. This process plays a significant role in the prevention of auto-immune conditions.

Lymph nodes are structured to optimize the coordination between the innate and active immune responses. The outer follicles house B cells, follicular dendritic cells, and macrophages. Dendritic cells that present antigens and activate T cells are found within the paracortex. The inner-most medulla contains B cells, T cells, and plasma cells. [2]

The spleen has a function similar to lymph nodes. T cells and B cells are located in the white pulp. Germinal centers within the white pulp are filled with memory cells, follicular dendritic cells, and macrophages. 

Function

Active immunity functions as an additional immunologic defense to eliminate infective pathogens from our body. The process is more energy-intensive compared to the innate immune response and is therefore reserved for pathogens not effectively removed by the body's initial defense. Immunity mounted by the active, antigen-specific response provides decades of protection against that antigen.

Mechanism

A 2-step activation process is required to prevent unnecessary or detrimental responses. Step one begins with CD4 helper T-cell interactions with dendritic cells. Dendritic cells will take up an antigen, process it, bind it to an MHC II molecule and present it on its cell surface. The T-cell receptor complex (TCR) on helper T cells recognize these MHC II-antigen complexes, bind, and become activated which allows for the second signal to occur. The second step of activation requires a B7 receptor on the dendritic cell to interact with the CD28 receptor on the helper T cell. This is important to note because B7 receptors are only expressed on activated dendritic cells. If the first signal occurs without the second, the T cell is inappropriately interacting with an unactivated dendritic cell and undergoes apoptosis. Destruction of these defective T cells eliminates self-reactive cells and improves self-tolerance. If all goes correctly and both the MHC-II and B7 receptors are expressed, the T cell is fully activated and ready to migrate out of the lymph node into circulation or to the B cell areas of the lymph node and spleen.

Activated helper T cells begin as TH0 cells and enhance immunity by releasing cytokines such as IL-2, IFN-gamma, and IL-4 to stimulate lymphocyte growth and activate more dendritic cells. If IL-12 is present (released from dendritic cells and macrophages), the TH0 cell will transform into a TH1 cell and releases IL-2, IFN-gamma, and TNF-beta which play roles in both the cellular and antibody responses. The production of TH1 cells is perpetuated by the release of IFN-gamma (also known as macrophage activation factor) which stimulates further synthesis of IL-12. TH1 cells activate macrophages, natural killer cells and CD8 cytotoxic T cells which are important for intracellular infections such as viral illnesses.[3]

Cytotoxic T lymphocytes (CTL) develop from CD8 T cells in response to cytokines released from TH1 cells and play a role in destroying virally infected cells and tumor cells. CTLs bind to their target cells via antigen presenting MHC I molecules. They destroy infected cells using perforin proteins which bore holes in the membrane and allow an influx of granzymes into the cell to promote apoptosis. CTLs can also trigger apoptosis through FasL (on T cells) and Fas (target cells) protein binding. [4]

If IL-12 and IFN-gamma signals are not present, TH0 cells become TH2 cells. The TH2 cells are activated by dendritic cells presenting MHC II-antigen complexes on their surface. Once activated, TH2 cells release IL-4, IL-5, IL-6 and IL-10 cytokines which stimulate a humoral (antibody) response. These cytokines promote B cell immunoglobulin class switching from IgM and IgD to IgG, IgE, and IgA. Antibodies play a role in eliminating infectious pathogens, preventing hematologic spread and providing future protection if re-exposed.

While the T cells are being activated, antigens also enter the lymphatics traveling to the lymph nodes and spleen where they interact with specific B-cell immunoglobulin receptors. The B cells ingest and process the antigen, bind it to an MHC II molecule and express it on their surface. Now, the activated TH2 cells can bind these B-cell which have a similar antigen receptor. Once bound together, TH2 cells signal the B cells to become plasma cells and produce immunoglobulins. Plasma cells will secrete IgM until cytokines from the TH2 cells prompt an isotype switch. Some of these B cells become memory cells and allow for long-term immunity. [3]

Active immunity utilizes cytotoxic T lymphocytes, TH1, TH2 cells, and activated B cells to target infections from multiple angles. CTLs destroy infected cells and the immunoglobulins produced by B cells target antigens in the bloodstream to bind and prevent them from reaching their target cells.

Clinical Significance

Mounting of an immune response after vaccination is dependent on active immunity. Toxoid vaccines, such as the tetanus toxoid vaccine, activate the immune response similar to antigens utilizing TH2 and B cells to stimulate the production of immunoglobulins against the toxoid. One downside to this method of vaccination is that it requires multiple doses to achieve high immunogenicity. Advantages include no chance of the vaccine causing the targeted disease or spreading to those without immunity.

Inactivated and killed vaccines also create immunity through interactions with B and TH2 cells but create a much broader cohort of immunoglobulins against many antigens. Dendritic cells ingest the entire organism, either an inactivated bacteria or a killed virus, digest it and present multiple, different antigenic fragments. This allows for the development of immunoglobulins specific to a number of antigens. Inactivated or killed vaccinations also require multiple doses to mount a strong response.

Polysaccharide subunit vaccines, such as the 23 polysaccharide pneumococcal vaccine, create a T-independent immune response. TH2 cells only respond to proteins, so the polysaccharide vaccines are unable to activate them. Instead, the polysaccharide molecules bind specific B-cell receptors with such high affinity they do not require T-cell activation. This leads to the production of IgM. Without TH2 involvement, production of IgG and memory B cells is limited. Immune responses can be strengthened by conjugating or attaching the polysaccharide vaccine to a protein. This allows for phagocytosis by dendritic cells, involvement of TH2 cells, and production of IgG and memory B cells.

Live attenuated vaccines such as the measles, mumps, and rubella elicit their immune response through intracellular pathways. Live, altered virions can enter cells via receptor-mediated endocytosis where they are degraded and presented by MHC I molecules on the cell surface. Cytotoxic T cells specific to those receptors bind and promote apoptosis. Long-term immunity is achieved when some of these cytotoxic T cells become memory cells. The mechanism behind the production of memory T cells is not well understood. In addition to this cytotoxic T cell response, TH4 and B cells will also create IgG and memory B cells. Live vaccines provide a defense for infected cells as well as free antigens in the bloodstream but, come with a risk of possibly contracting the targeted illness. [1]  

Our active immune system is essential for protection against infectious disease. It is important to understand how this system should work so that healthcare professionals can recognize and appropriately intervene when processes go haywire. Preventative health and vaccinations would not be as effective as they are today without the study of these complex mechanisms.


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Physiology, Active Immunity - Questions

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Which of the following vaccinations is NOT considered to confer active immunity?



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Which confers passive instead of active immunity?



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A 26-year-old male presents to the clinic with complaints of a painful "pimple" on the vermilion border of his lip for the past 24 hours. He reports experiencing a burning sensation in the area prior to noticing the pimple. Upon further inspection, there is a small cluster of pustules on an erythematous base. Which part of the active immune response is responsible for clearing this infection?



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Which of the following proteins are secreted as part of the active immune response?



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A 12-year-old boy presents to the clinic with complaints of a sore throat, rhinorrhea, and headache. The symptoms have been ongoing for three days. He denies any sick contacts, nausea, vomiting, abdominal pain, or diarrhea. On physical exam the patient's pharynx is erythematous, but no tonsilar exudates are present. Frontal and maxillary sinuses are non-tender to palpation. Tympanic membranes are translucent, and the cone of light is present bilaterally. Palpation of the neck reveals bilaterally enlarged and tender cervical lymph nodes. Which of the following is true regarding lymph nodes?



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Physiology, Active Immunity - References

References

Active and passive immunity, vaccine types, excipients and licensing., Baxter D,, Occupational medicine (Oxford, England), 2007 Dec     [PubMed]
McHeyzer-Williams M,McHeyzer-Williams L,Panus J,Pogue-Caley R,Bikah G,Driver D,Eisenbraun M, Helper T-cell-regulated B-cell immunity. Microbes and infection. 2003 Mar     [PubMed]
Kajino K,Kajino Y,Greene MI, Fas- and perforin-independent mechanism of cytotoxic T lymphocyte. Immunologic research. 1998     [PubMed]
Willard-Mack CL, Normal structure, function, and histology of lymph nodes. Toxicologic pathology. 2006     [PubMed]

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