Marco Histórico del cine en Bolivia
5.2. La llegada del cine a Bolivia y el periodo silente
L. Roy Eversole, DDS, MSD, MA
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bacteria and fungi have molecular motifs that bind to complement receptors on leukocytes, integrins, or extra-cellular matrix molecules. The mimicry then allows organ-isms to bind to host tissues and propagate in that milieu.
Once organisms have penetrated cells or have been phagocytized as intracellular parasites, they exert a variety of escape mechanisms that prevent them from being lysed. Some secrete hemolysins that destroy lyso-somal membranes; others synthesize proteins that pre-vent fusion with lysosomes. Certain specific bacteria, such as mycobacteria, possess cell-wall glycoproteins that are resistant to lysosomal digestion.
Endotoxin is present on the cell membrane of many bacteria. This molecule is a lipopolysaccharide (LPS) that has a wide range of inflammatory effects that include stimulation of proinflammatory cytokines from leukocytes. Such effects contribute to a robust leuko-cytic response that can result in tissue destruction. Exo-toxins are secreted by bacteria and are highly specific.
For example, the diphtheria toxin is a bimolecular com-plex. The protein A subunit interferes with host-cell metabolism by arresting protein synthesis. Many other organisms secrete exotoxins that interfere with host-cell metabolic processes. For example, intestinal pathogens secrete toxins that interfere with G protein signal trans-duction in host cells, leading to massive accumulation of fluids in the gut.
The shedding of bacterial antigens serves to bind antibodies and complement, allowing the infectious agent itself a form of sequestration and escape. Another group of virulence factors derived from bacteria are enzymes that can be tissue-destructive. Included in this group are the collagenases and glycosidases that lyse collagen and glycosaminoglycan extracellular matrix polymers, laminases, lectinases, and other proteases that degrade integrins. Complement inactivation by K antigens and binding of Fc regions on
immunoglobu-lin molecules by staphylococcal protein A are yet other virulence factors found in specific bacteria.
Viral virulence factors include envelope and capsid proteins that act as adhesion molecules and mediate viral entry into cells that express receptors for these adhesins. This molecular interaction is, in part, what governs cellular tropism by viruses. Viral proteins can alter host membranes making them porous or allowing cells to fuse with one another. As with bacteria, some viral proteins mimic normal cell chemistry and find ways of eluding the immune response. Early viral pro-teins interact with host-cell DNA and promote host-cell proliferation, viral nucleic acid integration (integrase enzymes) and viral replication by synthesis of DNA polymerase in the case of DNA viruses and reverse tran-scriptase in the case of RNA retroviruses. Once inter-nalized into the host cell, viral parasites usurp normal cell constituents for their own propagation and also result in lysis and necrosis of host cells. Viral proteins are integrated into major histocompatibility complex (MHC) class II molecules in antigen-presenting cells for immunorecognition and into MHC-I molecules which then become targets for cytotoxic T lymphocytes, which can then further destroy host cells that harbor virus.
This aids in viral elimination, yet also results in wide-spread host-cell destruction. Herpes group viruses are able to prevent MHC-I assembly and can hide inside cells without expressing antigen on the cell surface.
Most herpesviruses elaborate proteins that enable them to remain latent intracellular parasites. At a later point in time, other viral gene products are elaborated, awak-ening the virus from latency and promoting a recurrent lytic infection of host cells.
Host defenses
The flip side of virulence is host resistance. Following is a brief overview of host response to challenge by foreign proteins and glycoproteins that are present on microbial cell walls, envelopes, and capsids. The host defends against infectious diseases by mounting an immune response. The primary barrier to infection is the strati-fied squamous epithelium of the skin and mucous mem-branes. For many years, this barrier has been considered in the context of a physical barricade that prevents pen-etration of pathogenic microorganisms, thereby mitigat-ing their access to the connective tissues and vital organs. It is now well documented that the skin and mucosae are biochemical and immunologic organs. Fur-thermore, it is axiomatic that some infectious agents, particularly viral and fungal pathogens, actually use the epithelium for colonization and propagation.
All microbial agents possess surface proteins and glycoproteins that are recognized as “non-self” or
Table 12–2 Viral Virulence Factors Envelope/capsid adhesion molecules
Specificity for binding to host-cell membrane proteins Molecular mimicry
Cell membrane modification factors Intracellular molecular alterations
Specific tropism for selected cell types Enzyme and substrate piracy
Inactivation of host-cell protein synthesis Inactivation of host-cell DNA and RNA synthesis Propagation-induced lysis
MHC-I cell-surface presentation MHC-I sequestration
Latency-inducing viral proteins Early proteins, cell cycle activation MHC = major histocompatibility class.
“foreign” to the human host. The foreign molecules are referred to as antigens. This foreignness is the sine qua non of the host mechanism of defense. When a viral, bacterial, or fungal pathogen comes in contact with host tissues, it does so with a plan. This plan is to use the host as a substrate for self-propagation. As has been discussed, self-propagation takes place at the expense of host-cell integrity, thereby resulting in dis-ease. When host tissues are violated by microbial pathogens, a group of cells become activated and alert the host that a battle must be engaged. These cells are referred to as antigen presenting cells and are com-prised of intraepithelial Langerhans cells and migra-tory as well as fixed tissue macrophages. These ubiq-uitous cells are able to phagocytize, indiscriminately, foreign antigens and digest their molecular compo-nents by an enzymatic organelle known as the protea-some. The digested antigens are then attached to an MHC-II molecule and exteriorized on the cell surface (Figure 12–1). These phagocytes are then activated to motility and migrate via lymphatics to regional lymph nodes where they encounter lymphocytes that bear a specific receptor that recognizes the antigen in the con-text of the MHC-II molecule (class II restricted lym-phocytes). These lymphocytes are destined to help or induce the host immune response and are, therefore, termed helper-inducer lymphocytes. These lympho-cytes bear a cell-surface molecule that is their trade-mark, CD4.
The CD4 lymphocytes, so stimulated, peruse one of two specific pathways: Th1 and Th2. The pathway taken is governed by the nature of the pathogen anti-gens. Some organisms are eliminated more efficiently by Th1 stimulation; others are more effectively eliminated by Th2 pathway stimulation. These pathways are stim-ulated by certain chemical moieties, known as cytokines, synthesized by the antigen-presenting cell.
The Th1 pathway stimulates another subset of lympho-cytes that bear the surface-marker protein CD8. These lymphocytes are cytotoxic, able to directly destroy cells that are infected with virus or destroy cells that bear the foreign antigen on the membranes. The Th2 pathway involves the stimulation of a subset of lymphocytes that bear surface immunoglobulins, glycoprotein antibodies that bind to foreign antigens. These are known as B-lymphocytes, cells that can migrate into tissues and transform into plasma cells.
Once B lymphocytes are activated, they secrete spe-cific immunoglobulins that spespe-cifically bind to foreign antigens (Figure 12–2). There are five classes of
Antigen
MHC-II: antigen T-cell receptor
Macrophage
Immunoglobulins
B lymphocyte
CD8
cytotoxic T cell Th2
Th1 Mitogen
CD4 lymphocyte
IgG Infection late
IgM Infection early
IgA Mucous secretions
IgD Primative responses
IgE Immediate hypersensitivity
Figure 12–1 Immune response overview. Antigen-presenting cells interact with CD4 lymphocytes that diverge into Th1 and Th2 pathways to activate CD8 lymphocytes and B lymphocytes, respectively. MHC-II =
major histocompatibility complex class II. Figure 12–2 Immunoglobulin classes and functions.
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immunoglobulins (Ig): IgG, IgM, IgA, IgD, and IgE. IgM is the first antibody to be stimulated by an infection and is quickly replaced by B cells that secrete IgG. IgA is a unique antibody that is generated by lymphocytes in the intestines and is found in mucosal secretions, including breast milk, oral, nasal, pharyngeal, pulmonary, intesti-nal, and urogenital mucous membrane secretions. IgD is an early immunoglobulin that becomes replaced by oth-ers during maturation of the immune response to an antigen. IgE is protective against certain parasites and is the key antibody in allergic reactions that occur within minutes of exposure to antigen (immediate hypersensi-tivity). Antigens that are noninfectious, yet mediate an IgE response are termed allergens.
When antigens that trigger the Th2 cytokine profile select a Th2 pathway, B lymphocytes are selected for immunoglobulin synthesis. B cells carry receptors on their surface that recognize specific amino acid sequences on antigens. The receptors are immunoglob-ulins, and the antigenic sequences are known as epi-topes. Once specific B lymphocytes are bound to anti-gen, they transform into plasma cells that become immunoglobulin secretors (Figure 12–3). When viral, fungal, or bacterial antigens are the stimuli, the B cells secrete IgM and IgG into the serum with resultant hypergammaglobulinemia. If soluble antigens are pre-sent in the serum, Ig:Ag complexes, also known as immune complexes, form and may filter out into the tis-sues to cause a pathologic response. This response is
typically seen around vessel walls, forming an immune complex vasculitis. If the stimulatory antigen is an aller-gen, IgE-bearing B cells respond. The IgE antibody, referred to as reagin, has a binding site on mast cells and when allergenic epitopes are bound, mast cells degranu-late, releasing histamine and other vasoactive mediators that culminate in vasodilation, permeability, and edema.
In the context of immunity against infectious agents, the role of immunoglobulin is limited; the function of the antibody molecule is to bind the antigen and pre-cipitate it. To achieve microbial death, lysis, and elimi-nation, immunoglobulins require another group of active proteins. These proteins are collectively known as complement (Figure 12–4). The C1qrs trimolecular complex binds to an antigen that is already bound to its complementary IgG or IgM antibody. (There is an alter-native pathway that does not require IgM or IgG.) Frac-tions 2, 4, and 3 are then activated, and it is the bind-ing of C3 that initiates the inflammatory cascade by releasing C3-derived peptides known as cleavage prod-ucts. These peptides are biologically active, stimulating other complement fractions to form complexes (C5, 6, and 7 chemoattractants), causing mast cells to degranu-late (C3a, C5a anaphylatoxins), and coating microbial-cell walls with peptide fragments (opsonins) that facili-tate phagocytosis. The final complement components, C8 and C9, form the membrane attack complex, a reac-tion that eventuates in lysis of the infectious agent cell membrane. Thus, it is Ig with complement activation that results in the inflammatory response with edema, chemotaxis of leukocytes, phagocytosis, and lysis.
Another mechanism for microbial elimination is antibody-dependent cellular cytotoxicity. In this sce-nario, antibody binds to infectious agents or to infected host cells that express microbial antigens (Figure 12–5).
The immunoglobulin molecule, on the pole opposite its antigen-binding domain has chemical sequences that bind leukocytes. These sequences are located in the Fc region of immunoglobulin, and leukocytes that have adhesion molecules (Fc receptors) for this region of Ig.
Once bound, phagocytosis may proceed or leukocyte enzymes and oxygen free-radical species may then inac-tivate microbial propagation.
All of the aforementioned pathways involve B-cell activation, immunoglobulin synthesis, secretion and cir-culation within the blood, and propagation of inflamma-tion via complement pathways. Taken altogether, this is the humoral-mediated immune response (Th2). The cell-mediated immune (CMI) response is engendered, not by immunoglobulin, but by cytotoxic CD8 lymphocytes.
Cell-mediated immune response does not use circulating cell products (ie, Igs); rather the detrimental effects on microbial agents and infected host cells is mediated by the CD8 lymphocyte directly (Th1). In such reactions, these cytotoxic cells must be transported through blood to the
CD4 lymphocyte
Figure 12–3 The Th2 pathway involves activation of immunoglobulin-secreting B lymphocytes and plasma cells.
site of the infection; such responses usually require up to 48 hours and are, therefore, termed delayed immune responses. Once CD8 lymphocytes contact cellular anti-gens, they bind to them by virtue of specific T-cell recep-tors (Figure 12–6). These T-cell receprecep-tors have the same intricate specificity for antigenic epitopes as do the B-cell immunoglobulin receptors. The antigen is engaged in the context of the cell-surface molecule MHC-I, and there-fore, cytotoxic T cells are MHC-I restricted. Once the lymphocyte binds to the infected cell, a class of cytokines termed perforins is released, and these proteins mediate cell lysis of the target cell that harbors the MHC-I:Ag complex. Microscopically, CD8 reactions are character-ized by chronic inflammatory cell infiltration.
At the outset it was mentioned that the epithelium of the skin and mucous membranes serves as a physical, immunologic, and biochemical barrier to infection. It is
now well documented that keratinocytes are a vital component of the immune system. These cells elabo-rated inflammatory cytokines, leukocyte mitogenic fac-tors, adhesion molecules for leukocytes, and chemo-attractants. All of these functions are stimulated when a pathogen passes into the epithelial layers.
Immunoglobulins and complement more efficiently eliminate bacterial infections whereas the cellular limb of the immune response is more efficacious for viral and fungal infections. In most infectious diseases, both limbs of the immune response are active, yet one appears to take precedence over the other, depending upon the nature of the offending organism. Recall that both humoral and cellular immunity require induction by antigen-presenting cells and CD4 lymphocytes. It is the CD4 lymphocyte that is the target for the human immunodeficiency virus (see Chapter 14). As CD4 cells
Fc region, IgG
C1qrs
C2, C4
C5, 6, 7
Chemotaxis Opsonin Ag
C8, 9
Histamine
Dilation increased permeability Anaphylatoxins Lysis
Phagocytosis
Edema
Leukocyte emigration C3
Figure 12–4 The role of complement in the elimination of pathogens and pathogen-infected host cells.
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are progressively eliminated by viral-induced and CD8 cell-induced lysis, the ability to mount an immune response to new antigens becomes impaired, leading to the emergence of opportunistic infections.
Suggested reading
Eversole LR. Defense. In: Eversole L, Leider A, Merrell P, Car-penter W, eds. General pathology and medicine in dental practice. 3rd Ed. Stockton, CA: University of the Pacific Press, 2000:1–60.
Lamont AG, Adorini L. IL-12: a key cytokine in immune reg-ulation. Immunol Today 1996;17:214–7.
Murray JS. How the MHC selects Th1/Th2 immunity.
Immunol Today 1998;19:157–63.
Romagnani S. The Th1/Th2 paradigm. Immunol Today 1997;
18:263–6.
Samuelson J, von Lichtenberg F. Infectious diseases. In: Cotran RS, Kumar V, Robbins SL, eds. Robbins pathologic basis of disease. 5th Ed. Philadelphia: WB Saunders, 1994:305–19.
Strober W, Kelsall B, Fuss I, et al. Reciprocal IFN-gamma and TGF-beta responses regulate the occurrence of mucosal inflammation. Immunol Today 1997;18:61–4.
B lymphocyte / plasma cell
PMN
IgG
MHC-I:Ag
Lysosomal enzymes, ree radicals fr
Lysis
Phagocytosis Macrophage
Fc receptors
CD8 cytotoxic lymphocyte
Perforins
Lysis Viral Ag
expressed T-cell
receptor
Figure 12–6 The Th1 pathway involves binding of CD8 lymphocytes to target antigens culminating in release of cytolytic perforins.
Figure 12–5 Antibody-dependent cellular cytotoxicity: phagocytes bind to Fc regions of Igs that are, in turn, bound to antigen. PMN = poly-morphonuclear neutrophil leukocytes; MHC-I = major histocompatibility complex class I.
117 The human herpesviruses (HHV, numbered 1 through 8)
represent a large group of DNA viruses that share some common biologic features that account for a great deal of oral pathology. Human herpesvirus infections often lead to acute oral signs and symptoms, are a challenge to diagnosis, and are frequently difficult to treat. This fam-ily of viruses includes the herpes simplex viruses (HSV) 1 and -2), the varicella-zoster virus (VZV) (HHV-3), Epstein-Barr virus (EBV) (HHV-4), cytomegalovirus (CMV) (HHV-5), and the relatively more recently iden-tified viruses, HHV-6, HHV-7, and HHV-8. Because of their different expressions of disease, each of the herpes family viruses is discussed separately.
Although the occurrences of HHV in both health and disease are worldwide, their exact prevalence is uncer-tain. Because their modes of clinical expressions differ, HHV infections pose frequent and common global prob-lems for both patients and clinicians. The worldwide problem of immunosuppression has an effect on the fre-quencies and control of HHV oral disease. The details of frequency, severity, diagnosis, and treatment of HHV and immunosuppression are covered in detail in Chapter 14.
Human herpesviruses have a large spectrum of asso-ciated pathologic effects on cells and tissues. They are associated with both acute and chronic infections as well as neoplasia. Whereas the history and clinical features sometimes allow an accurate diagnosis, at other times,
Molecular and pathologic correlates of disease, 117 Herpes simplex viruses, 118
Clinical features, 119
Hand, Foot, and Mouth Disease, 125
Sol Silverman, Jr, MA, DDS, and L. Roy Eversole, DDS, MSD, MA
sophisticated laboratory testing is required to identify and classify the specific HHV member. Following identi-fication, the management regarding initial treatment, recurrences, and prevention often becomes a challenge.
Molecular and pathologic correlates of disease
The human herpesviruses are comprised of a DNA genome surrounded by an icosahedron protein capsule that is enclosed within an envelope. The average dimen-sion is about 200 nm. These viruses are subclassified into alpha, beta, and gamma subtypes according to their virulence in tissue culture. Human herpesviruses 1, 2 (simplex types), and 3 (varicella-zoster virus) belong to the alpha group, Epstein-Barr virus (HHV-4) to the gamma group, and cytomegalovirus (HHV-5) is a mem-ber of the beta group. Human herpesviruses 1 and 2 possess envelope proteins that bind to plasma mem-brane receptors on keratinocytes and neurons. Upon binding, the virions enter the cytoplasm by endocytosis, and the receptors can then recycle back to the cell mem-brane (Figure 13–1). Virions under genetic control uncoat, and the DNA enters the nucleus.
Replication ensues within the nuclear envelope, and transcription of proteins takes place in the cytoplasm