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Immunology/Microbiology for ID

Are Microbial Symptoms "Self-inflicted"?: The Consequences of Immunopathology

Rosenthal, Ken S. PhD

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Infectious Diseases in Clinical Practice: November 2005 - Volume 13 - Issue 6 - p 306-310
doi: 10.1097/01.idc.0000189086.49218.fd
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Although many of the symptoms of microbial diseases are caused by the damage to cells and tissue by the replication, growth, and products (eg, toxins) of the infecting microbe, very often, the signs and symptoms that we suffer during our infections are the consequences of our innate or immune responses combating the microbial invaders on the battlefield that is our body. Once initiated, these responses are oftentimes difficult to control and can cause peripheral damage. Hence, the title question, "Are microbial symptoms self-inflicted?" This being the first article in this section, I decided to have some fun with it and continue with the battlefield analogy before discussing specific examples of the disease signs and symptoms which result from the "self-inflicted" protective responses to microbial infection.


Possibly, the most common consequence of the activation of protective responses to microbial infection is being tired. Our protective responses, including the innate and immune responses, act very much like a military defense against infection. Similar to the military, it has one of the highest priorities for energy supplies in the body, second only to the brain. When war is declared, whether on a national or a microbial invader, energy resources are focused on mounting an effective defense to oust the invader. The expansion of an immune response to infection is accompanied by the rapid deployment of neutrophils, and the growth and multiplication of replacement neutrophils, the expansion of antigen-specific T cells and B cells, and large increases in production of proteins as part of the acute phase, innate, and immune responses. All of these actions require energy in the form of glucose (depriving the brain of some of its precious supply) and, ultimately, ATP. To give you an example of the magnitude of the response to infection, the number of CD8 T cells specific for a single microbial antigen may increase as much as 100,000 times, and this must be multiplied by the large number of antigens expressed by each microbe. Similar expansions in cell number are occurring for CD4 T cells and B cells, and these changes occur within a relatively short period. In addition, every burst of oxygen-dependent killing of bacteria in a neutrophil or activated macrophage is accompanied by the depletion of reduced energy stores in the form of nicotinamide adenine dinucleotide phosphate, which is generated by metabolism of glucose.


The initial innate defenses evolved with the ability to sense foreign invaders and distinguish microbes by recognition of pathogen-associated molecular patterns (PAMPs), which are repetitive structures (lipopolysaccharide, peptidoglycan, teichoic acid, and flagellin) that either decorate the surface of the microbe or are inherent in the structure of the genomic DNA (unmethylated cytosine-guanosine sequences) or RNA. These structures can trigger boobytrap-like host defenses, for example, complement, and activate the local cellular police and militia to initiate the attack and send the alarm for reinforcements.


Complement (C′) and other proteins are activated by some of these PAMPs. The alternate (properdin) or mannose-lectin-activated complement pathway is triggered by bacterial cell surfaces. Activation of the complement system can destroy the invader and initiate a signal to bring in the troops. Complement shoots holes in the microbe causing leakage of its contents into the surrounding fluid. The C3a and C5a components of C′ open up the capillary highways (anaphylotoxins) and set out molecular guideposts (chemotaxins) to allow the reinforcements, in the form of fluid (edema) and leukocytes, to access the site of infection. These chemotaxins and anaphylotoxins are very helpful at the local level, but when administered at a systemic level, they contribute to the pathogenesis of sepsis. Excess fluid loss results in shock, and the inappropriate activation of complement can cause tissue damage.


The first defenders to the site of infection follow a chemotactic pathway established by the spoor of characteristic molecules from the microbial invaders and the molecular cries for help from the local cellular population. Neutrophils are the first to respond and diapedese through the capillaries to the microbial battlefield. The neutrophils surround, gobble, and then bleach and poison the enemy with activated oxygen and halide molecules. In addition, granules containing antimicrobial enzymes and proteins release their contents into the phagolysosomes to kill and degrade the microbe. The granules also release their contents outside the cell like a poison gas, killing some of the extracellular microbes but, unfortunately, innocent bystander cells, as well. Other inflammatory substances, such as products of the lipoxygenase and cyclooxygenase pathways, histamine, the kinin system, and cytokine proteins (discussed later), not only expand the antimicrobial activities, but also cause peripheral damage as a byproduct. Upon completion of their task, the neutrophils are unable to leave; they die and leave their carcasses, like expended and blown-up tanks, on the microbial battlefield. The accumulation of dead cells and fluid becomes pus.

Mononuclear Phagocytes

Monocytes are next to enter the fray. They facilitate the action of the dendritic cells (DCs) that are localized in the tissue (Langerhans cells). The monocytes differentiate into DCs and macrophages. All of these cells respond to the presence of microbes in several ways. These cells are constantly surveying their surroundings with cell surface receptors and by "tasting" the proteins in the surrounding fluid by phagocytosis and pinocytosis. PAMP-specific receptors, termed Toll-like receptors (TLR; Table 1),1-3 on their cell surface and within the phagocytic vesicles, detect the characteristic patterns of microbes. Triggering of these receptors activates the cells and the production and release of molecular warning systems, cytokines. The cytokines include interleukin (IL) 1, IL-6, and tumor necrosis factor (TNF) α. These cytokines, combined with the C3a and C5a components of complement, change the "current threat level of the body" from green to yellow, orange, or red. They do this by increasing fever, by activating the liver to produce acute phase protective proteins, and by enhancing the protective activity of endothelial cells and macrophages. However, in severe infections, large amounts of TNF-α and IL-1 are produced and will activate these and other responses at a systemic level. TNF-α and IL-1 are the major causes of the pathogenesis of sepsis and septic shock.

PAMPs and the Receptors That Activate Host Responses

Dendritic Cells and Their Cytokines

Immature DCs hanging out at the local site are very sensitive to PAMPs and respond with production of interferon (IFN) α and IL-12. IFN-α is also produced and released by virus-infected cells. The IFN-α, like Paul Revere, binds to other cells warning them of imminent virus infection. This promotes an antiviral response in local cells which, upon activation by the presence of a virus, will put cellular protein synthesis on strike to prevent virus replication. IFN-α also sends a signal to activate more systemic antiviral responses, which unfortunately leads to the onset of "flulike symptoms."

IL-124 and IFN-α activate natural killer (NK) cells. NK cells are a local bully squad of cells which are programmed to kill virus-infected and other cells unless the cells can make the appropriate molecular handshake with the KIR (killer cell inhibitory receptor). Unfortunately, there is peripheral damage associated with the NK cell response, and these cells seem to become more belligerent as we get older (up to a certain age). This may be a reason why varicella zoster virus and Epstein-Barr virus infections of teens and adults are much more severe than for younger children.


TH1 Responses

DCs provide the link between the local innate responses and the immune responses.5,6 Upon activation at the microbial battlefield, DCs mobilize and carry within themselves microbial proteins and process them into the small peptide language understood by the T-cell army. These peptides occupy major histocompatibility complex molecules on the DC surface and are displayed to T-cell receptors in conjunction with other signals that override the instructions for a peaceful existence to promote activation of immune warfare. In conjunction with IL-12, the DCs promote CD4 and CD8 T cells to produce cytokine molecular messages as part of a TH1 (first, local, and cellular) response. These cytokines include IL-2, to expand the numbers of the lymphocytic army, and IFN-γ, to promote early local responses to the infection. Activation of TH1 responses is often associated with inflammation and, if uncontrolled, includes autoimmune diseases such as multiple sclerosis and Crohn disease.

IFN-γ is very important for the control of viral, fungal, and intracellular bacterial infections.7-9 IFN-γ reinforces the production of IL-12 to solidify the TH1 response. IFN-γ also promotes the production of a specific subtype of immunoglobulin G which facilitates complement. Most significantly, IFN-γ converts macrophages into more effective fighting machines. IFN-γ makes macrophages angry! And angry macrophages become killer cells, killing phagocytosed microbes. They also release antimicrobial substances and nitric oxide into the site. Similar to the effects of neutrophils, the activated macrophages cause tissue damage and inflammation through the release of nitric oxide, oxygen metabolites, proteases, and other degradative enzymes. Crude attempts at repair of the injury lead to fibrosis. If these actions cannot eliminate the microbe, then IFN-γ will stimulate the macrophages to build a wall around the microbial invader, for example, Mycobacterium tuberculosis, producing a granuloma. These granulomas may limit the microbial growth but are like an unexploded mine which will go off in the absence of IFN-γ during immunosuppression.

Sometimes, the initiation of the IL-12-IFN-γ cycle can activate rogue TH1 cells which are directed at host proteins. These rogue TH1 cells can be activated by microbial structures resembling host proteins, and initiation of damage by friendly fire may result in the development of autoimmune diseases such as multiple sclerosis or Crohn disease.10

TH2 Responses

After the microbe or microbial antigen has spread from the initial site of invasion and the immune system has identified the invader, antibody responses are activated. These responses are directed by TH2 (second, later, systemic, and antibody) CD4 T cells which release the cytokines IL-4, IL-5, IL-6, and IL-10 to promote B-cell growth, differentiation, and maturation of antibody production. Antibodies are molecular smart bombs directed toward very specific structures on microbes and toxins. The antibodies can envelop the viruses and toxins neutralizing their weaponry by preventing them from binding to their target receptors. Antibody bound to a microbe can also activate the attack mechanisms of complement or antibody-dependent cellular cytotoxicity by NK cells. Antibody can also mark the target for elimination and clearance by macrophages and other cells (opsonization). Antibodies are especially important to seek and control microbes that have escaped the initial battleground and are spreading through the highways of the blood system. Unfortunately, if there is a lot of antigen present that can form antibody-antigen complexes, as is the case of hepatitis B virus (HBV) infection, immune complexes build up and clog the small capillary byways of the body, and this activates the tissue-destroying functions of complement.

Premature activation of TH2 responses can be very detrimental. If the TH2 mode of warfare is initiated prematurely, then the local cellular TH1 responses will be inhibited, allowing some types of infection (eg, intracellular microbes) to progress.

After the infection is controlled, many of the unneeded immune cells conveniently commit hari-kari (apoptosis), whereas other cells return to their bases in the lymph nodes, bone marrow, and spleen with the knowledge and memory of the invader so that a future response can be faster and more effective.


The innate and immune responses to infection are essential for our survival, but as indicated previously and with more following examples, there is a price to be paid for the actions of our host defenses (Table 2). For some infections, this results in the elimination of the microbe, resolution of the infection, and the end of the disease. However, in other cases, such as the postinfectious encephalitis that accompanies measles and other viral infections, an overzealous immune response causes damage to an essential and difficult to repair tissue after the virus has already been controlled. In the next section, we will discuss more examples of infectious diseases for which the symptoms are "self inflicted," starting with examples of the consequences of innate responses and then transitioning to those involving immune responses.

Examples of Self-inflected Disease Symptoms

Innate responses, especially by complement and neutrophils, are important for controlling bacterial infections. During bacterial infection, especially gram-negative bacteria, large portions of their cell wall are shed into the body. Release of the lipopolysaccharide or lipooligosaccharide component of the gram-negative outer membrane stimulates endotoxin reactions. Upon release from the bacteria, the lipid A portion binds to the TLR4 and CD14 molecules on the surface of macrophages, monocytes, and DCs and activates a cascade of events resulting in the release of IL-1, IL-6, TNF-α, and other molecules. At a local level or for a limited infection, these responses are helpful, but for a bacteremia, these responses are systemic and can generate high fevers, capillary leakage, hypotension, shock, and disseminated intracellular coagulation. For example, the lipooligosaccharide of Neisseria meningitidis is readily released, and innate responses induced by the lipooligosaccharide promote fever, shock, and the production of petechiae and ecchymoses culminating in Waterhouse-Friderichsen syndrome. Even the successful antimicrobial killing of these bacteria (as in treatment of meningitis) can be detrimental by producing bacterial fragments which can provide more stimuli for these responses and exacerbate the disease. Other microbial components that stimulate TNF-α production cause many of the endotoxinlike consequences, especially fever. These include lipoarabinomannan of mycobacteria and zymosan of yeasts, and some of the exoantigens form plasmodia.

Superantigen toxins induce an even greater activation of immune functions than endotoxin. Staphylococcus aureus toxic shock syndrome toxin 1, staphylococcal enterotoxins, and erythrogenic toxin A or C of Streptococcus pyogenes activate a mixed population of CD4 T cells in a generic antigen-free manner by clamping major histocompatibility complex II molecules on antigen-presenting cells to T-cell receptor molecules on the T cell without requiring antigen. This results in activation of as much as 20%-30% of T cells, massive release of cytokines, unregulated activation of innate and immune responses, and loss of specific T-cell clones and their immune responses. The consequences are devastating to the patient with fever, hypotension, rash, and multiple organ system involvement. The disease results from the cacophony of responses to the cytokines released by the activated T cells.

Stimulation of IFN production by viruses, especially RNA viruses, triggers the classic flulike symptoms, which are the consequence of a respiratory infection or the prodrome for many viruses during the viremia phase of the infection. Malaise, myalgia, and fever associated with influenza, rhinovirus, and other respiratory viruses and the viremic phase of arboencephalitis viruses are the consequence of IFN-α production. These symptoms are also the side effects of IFN therapies for HBV, hepatitis C virus, and other diseases.

Induction of cell-mediated immune responses is definitely necessary for recovery from most virus infections but oftentimes is also the source of pathogenesis. Complete recovery from HBV infection requires the immune-mediated consequences that produce the icteric signs associated with classic hepatitis disease. HBV, hepatitis C virus, and even hepatitis A virus are very good parasites and not very cytolytic. Resolution of the infection requires cell-mediated immune lysis of the infected cells with painful consequences. The mild outcomes of HBV infection of children and others often indicate an inability to resolve the infection and result in chronic disease. The large quantity of HBsAg in the blood of HBV patients may promote immune complex formation and induce complement-mediated damage. Fulminant hepatitis or immune complex diseases such as glomerulonephritis or polyarteritis nodosa may be a resultant sequelae.

The mononucleosis associated with Epstein-Barr virus, cytomegalovirus, or even the initial phase of HIV infection is due to an excessive cellular response to the infection. T cells proliferate in response to the infected B or T lymphocytes, or myeloid cells initiating a civil war of lymphocyte against lymphocyte. The massive cellular proliferation takes a great deal of energy and causes swelling of immune organs. To a lesser degree, the pathological swelling of lymph nodes after Haemophilus ducreyi, Sporothrix schenckii, or mumps virus is also the result of an overwhelming lymphocytic response to infection. These microbes home to lymph nodes where they activate proliferative responses.

An overactive humoral response can also result in pathogenic responses. The presence of large amounts of microbial antigen can result in the development of immune complexes which can stimulate fluid-phase (type II) and cellular (type III) complement-mediated hypersensitivity reactions. Hemolytic anemia during the blood stage malaria results from activation of complement lysis of erythrocytes decorated with antibody bound to malarial antigen. Glomerulonephritis can result from the activation of complement, polymorphonuclear neutrophils, macrophages, or NK cells (antibody-dependent cellular cytotoxicity) by immune complexes containing streptococcal, HBV, or malarial antigens trapped in the capillaries of the kidney. Similarly, farmer's lung can result from the chronic inflammation that results from inhalation of fungi.

Many rashes are due to the immune response to the infection rather than direct microbial pathogenesis. For example, the rashes associated with measles, human herpesvirus 6, parvovirus B19, and even Borrelia burgdorferi are immune-mediated. For human herpesvirus 6 and parvovirus B19, the rash occurs after the infection has been resolved and is the result of immune complexes in the skin. For measles and rubella, the rash is a T cell-mediated hypersensitivity reaction to viral antigens in the skin.

Inflammatory joint disease and arthritis accompany or follow many viral or bacterial infections. In adults, in addition to the rash associated with B19 and rubella viruses or as part of Lyme disease caused by B. burgdorferi, immune complexes with microbial antigens will also cause arthritis.

In some cases, the immune system is tricked by microbial mimicry into generating cellular and humoral autoimmune responses. Tissue damage results from cell and antibody responses to microbial proteins that share epitopes with human proteins. Inflammatory heart disease or rheumatic fever may result from antibodies generated against bacterial proteins that resemble cardiac myosin, such as the streptococcal M protein or the 60-kd cysteine-rich outer membrane protein of Chlamydia trachomatis.10 Cross-reactive responses to oxidized low-density lipoprotein induced by Streptococcus pneumoniae infection may contribute to atherosclerotic plaque formation.11 Autoimmune diseases such as type 1 diabetes or multiple sclerosis may result from T cell-mediated responses to viral peptides that resemble a pancreatic protein or myelin.12,13

The potential for "self-inflicted" disease is also an important consideration in the development of vaccines. An early inactivated virus vaccine for respiratory syncytial virus (RSV) was a failure because the disease was exacerbated in vaccinated children. For RSV, an excessive cell-mediated response or humoral response can result in enhanced disease.14 For the pneumoviruses (RSV and metapneumovirus), more severe disease is related to the formation of antibody-RSV immune complexes.15 TH2 responses producing antibody, rather than cell-mediated responses, would be generated by the inactivated RSV vaccine, and these would prevent activation of protective TH1-related cellular responses and promote immune complexes to exacerbate disease. Similarly, the presence of maternal antibody to RSV is among the many theories for why some children have more severe disease than others.14

As with any battle, a more effective quicker means of controlling the enemy will minimize the size of the response that is mounted against the invader and the extent of the peripheral damage that results from the warfare. In most cases, the efficiency of our innate and immune responses toward controlling a microbial infection determines our survival. Being tired, having the sniffles, or even repairing lung damage after varicella zoster virus pneumonia is the price to be paid for surviving a microbial infection.


1. Kopp E, Medzhitov R. Recognition of microbial infection by Toll-like receptors. Curr Opin Immunol. 2003;15:396-401.
2. Medzhitov R, Janeway CA Jr. Decoding the patterns of self and nonself by the innate immune system. Science. 2002;296:298-300.
3. Hopkins PA, Sriskandan S. Mammalian toll-like receptors: to immunity and beyond. J Clin Exp Immunol. 2005;140:395-407.
4. Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nature Rev Immunol. 2003;3:133-146.
5. Palucka K, Banchereau J. How dendritic cells and microbes interact to elicit or subvert protective immune responses. Curr Opin Immunol. 2002;14:420-431.
6. Kapsenberg ML. Dendritic cell control of pathogen-driven T-cell polarization. Nat Rev Immunol. 2003;3:984-993.
7. Rosenzweig SD, Holland SM. Defects in the interferon-gamma and interleukin-12 pathways. Immunol Rev. 2005;203:38-47.
8. Pulendran B. Modulating TH1/TH2 responses with microbes, dendritic cells, and pathogen recognition receptors. Immunol Res. 2004;29:187-196.
9. Schroder K, Hertzog PJ, Ravasi T, et al. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75:163-189.
10. Wucherpfennig KW. Mechanisms for the induction of autoimmunity by infectious agents. J Clin Invest. 2001;108:1097-1104.
11. Binder CJ, Hörkkö S, Dewan A, et al. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med. 2003;9:736-743.
12. Honeyman MC, Stone NL, Harrison LC. T-cell epitopes in type 1 diabetes autoantigen tyrosine phosphatase IA-2: potential for mimicry with rotavirus and other environmental agents. Mol Med. 1998;4:231-239.
13. Wucherpfennig KW, Strominger JL. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell. 1995;80:695-705.
14. Openshaw PJM, Tregoning JS. Immune responses and disease enhancement during respiratory syncytial virus infection. Clin Microbiol Rev. 2005;18:541-555.
15. Polack FP, Teng MN, Collins PL, et al. A role for immune complexes in enhanced respiratory syncytial virus disease. J Exp Med. 2002;196:859-865.
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