In the past three decade, the progress in understanding the complex pathways of pathophysiology of asthma is as a result of collaboration from various interdisciplinary of physiologists, pathologists, immunologists, allergists. Occupational asthma occurs as a result of various exposure to sensitizing agent particularly in a work-related environment rather than stimuli exposed to outside workplace. Occupational asthma has been attributed as the cause of about 12% of adult asthma and also in industrialized countries, occupational lungs disease is one of most common consequences of occupational asthma . In general, two type of occupational asthma are recognized namely immunologic occupational asthma, that develops after a latency length of time of exposure, essential for possessing immunologic sensitization to the aetiological agent and non immunological occupational asthma that occurs after acute exposure to irritants in high concentrations which is less common normally called irritant-induced asthma(Bernstein I L et al 2006 and Mapp C E et al 2005). Over 300 known causal agent of occupational asthma which can be natural or artificial chemicals are recognized and are categorized into two main groups namely high-molecular-weight(≥ 5,000 Da) and low- molecular-weight(< 5,000 Da) agents. Proteins which are from animal or vegetable source are examples of high- molecular -weight agent that acts through an IgE mediated mechanism and inorganic and organic compounds (chemicals) are examples of low- molecular- weight agent which also acts through both IgE dependent and IgE non-dependent mediated mechanism. In most workplace, inhalation agents are responsible for asthma of relatively small group of exposed workers. Multiple genetic, environmental and behavioral influences can result in occupational asthma which can be recognized clinically due to the serious medical and socioeconomic consequences that is known with the condition. It is important to note that the level of exposure and route of exposure at the workplace with other environmental factors plays vital role in the initiation of occupational asthma. In recent data provided by Maestrelli P. et al 2006 and Sastre J. et al 2003 indicate that low-molecular-weight chemicals are responsible for more new cases of occupational asthma caused by sensitization. There is also controversies about many aspect of the pathophysiology of occupational asthma. The important low-molecular-weights chemicals that am going to be considering are acid anhydrides, plicatic acid (from western red cedar), polyisocyanates, colophony fume, metals such as persulfate salts, chlorinated platinum salts, and acrylates etc.
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BASIC PRINCIPLES OF IMMUNOLOGIC MECHANISMS OF OCCUPATIONAL ASTHMA There are functionally two separate arms of the system; antibody and cellular. B cells secrete and produces specific humoral antibodies while T lymphocytes regulates B cell function by helper and suppressor functions, regulate delayed hypersensitivity responses and deal with several cellular toxicity. T cells only recognizes already processed soluble antigen by antigen presenting cells (APC) in the groove of the major histocompatibility gene complex (MHC) molecule (Mcwilliam As.et al 1998 and Edgeworth JD.et al 1998). Suppressor/cytotoxic CD8+ cells recognizes antigen that binds to class I MHC molecules while Helper CD4+ T cells recognizes antigen that binds to class II MHC molecules. Dendritic cells present in the epithelium of airways are mainly for sensitization of the airway and they also capture allergens and process them. Afterwards moves to the local lymph nodes and peptide epitopes selected are presented to the allergens in the groove of MHC class II surface molecules and then to T cell receptor of CD4+ T cells. Allergens uptake are the function of the high affinity IgE receptors (FCεRI). ThO cell differentiation shift towards a T-helper cell 1(Th1) or T-helper cell 2(Th2) phenotype with interleukin IL-12 production by dentritic cells which causes Th1 and interleukin IL-4 to produce Th2 responses which is determined by the cytokine mileau at the time of antigen presentation. There is also functionally Th2-like lymphocytes that express many surface protein CD30 in the peripheral blood and tissues of atopic individuals(Corrigan CJ.et al 1989) and these cells produces interleukin IL-4 and IL-5 which is believe to play a vital modulating role in both IgE secretion and eosinophil assembling/activation at tissue level(Kay AB.et al 1997,Del Prete G.et al 1998 and Krug N.et al 1997). In genetically prone individual, there is a shift by antigen presentation to ingenuous T-helper cell O(ThO) CD4+T cells to Th2-like cells that has the ability to produce cytokines encoded in the long arm of chromosome 5 by cluster of gene like interleukin IL-4, interleukin IL-5,interleukin IL-9,and interleukin IL-13. The interaction between B-cell processed allergens and specific Th2-like T cells result in isotype switching to specific IgE, this process is made better by accessory molecule amplifers (CD40/CD40L and CD28/B7.2) that initiates increase production of interleukin IL-4 and interleukin IL-13 and consequently reduces signaling through the STAT 6 transcription factor(Monticelli S.L.D.et al 1998). Antigen activation causes the T lymphocytes produce numerous cytokines that attract, activate and contribute to progress of growth and differentiation of leukocytes which makes activated CD4+ Tcells inflammatory cells and helpers cells as well, for the secretion of humoral antibodies by B-cells. Repeated exposure after induction of sensitization allergen to same allergen results in increase of Th2 like response with secretion of inflammatory cytokines like granulocyte-macrophage colony-stimulating factor(GM-CSF), interleukin IL-3, interleukin IL-4, interleukin IL-5, interleukin IL-9, interleukin IL-13, and β-chemokines which are characteristic of chronic eosinophilic airway inflammation in asthma and IgE isotype switching. In parallel, allergens can also starts airway inflammation through cross-linking of surface IgE on masts cells by a separate pathways that induce and prolong inflammatory cascade that result in asthma.
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POLYISOCYANATES AND THEIR PREPOLYMERS The common isocyanates that causes occupation asthma are toluene diisocyanates(TDI), hexamethylene diisocyanate(HDI), 4-4-diphenylmethylene diisocyanates(MDI)(Butcher et al,1993). IgE non-dependent cellular mechanism is probably means by which isocyanates induces occupational asthma without the initiation of specific IgE antibodies(Sastre J.et al 2003) but it is not fully understood although they have clinical and pathologic features of immunologic asthma, which also shows that they probably acts through IgE dependent mechanism. Studies done by Cartier A et al 1989 have shown that induced asthma by HDI and MDI have Specific IgG antibodies that are more important IgE antibodies. Polyisocyanates can also induce occupational asthma by innate immune responses.
METALS Metals like nickel, chromium, cobalts are also example of chemicals that induce occupational asthma by IgE non-dependent cellular mechanism. Examples are potassium dichromate, nickel sulfate, cobalt chloride.
COLOPHONY FUMES The immunologic mechanism by which colophony fumes induce occupational asthma after a latency period have not yet been fully proven(Bernstein I L et al 2006 and Mapp C E et al 2005).
ACID ANHYDRIDES This chemical agent of low molecular weight acts through an IgE-mediated reaction by causing the formation of specific IgE antibodies that usually act as haptens but combines with autologous or heterologous proteins first to produce a functional antigens. The reaction between the allergens and IgE leads to Specific IgE antibody on the surface mast cells, basophils and macrophages, eosinophils, dendritic cells, platelets forms cross-linking with allergens that results in cascades of events that cause influx and activation of inflammatory cells. Subsequently, there is synthesis of predetermine inflammatory mediators or new inflammatory mediators formed, that then coordinate the inflammatory process that results in asthma. Acid anhydrides examples are tri-metallic anhydride, methyl tetrahydrophthalic anhydride, himic anhydride, hexahydrophthalic anhydride, tetrachlorophthalic anhydride
PLICATIC ACID (FROM WESTERN RED CEDAR) All the manifestations of non atopic/intrinsic occupational asthma caused by this chemical may not be explain by IgE-dependent mechanisms. Walker et al 1992, Del Prete et al 1993 and Maestrelli et al 1994 found that intrinsic asthmatic individual have CD4+, CD8+ and memory T cells in their peripheral blood which on activation produces interleukin IL-5 in bronchoalveolar lavage fluid and also that T-lymphocytes from peripheral blood of individual induced by red cedar produce interleukin IL-5 and interferon-γ( IFNγ) after stimulation with plicatic acid and human serum albumin. They acts through both IgE dependent mechanism and IgE non-dependent mechanism which is not fully understood.
COMPLEX PLATINUM SALTS They also acts through an IgE-mediated reaction like acid anhydride by causing the formation of specific IgE antibodies that usually act as haptens but combines with autologous or heterologous proteins first to produce a functional antigens. The reaction between the allergens and IgE leads to Specific IgE antibody on the surface mast cells, basophils and macrophages, eosinophils, dendritic cells, platelets to forms cross-linking with allergens that results in cascades of events that cause influx and activation of inflammatory cells. Subsequently, there is synthesis of predetermine inflammatory mediators or new inflammatory mediators formed that then coordinate the inflammatory process that result in asthma. Example of complex platinum salt is platinum halide salt.
OTHER EXAMPLES OF CHEMICALS Complex amines, some acrylates like methyl methacrylate, Aluminum potroom , Azodicarbonamide etc also induce occupational asthma by IgE non-dependent cellular mechanism .
CONCLUSION Mechanism by which low molecular weight agents cause occupational asthma remains uncertain to great extent. Data available suggest that asthma that occurs in workplace caused by low molecular weight compounds can be different from those involved in atopic asthma because of the subset of T-cells and cytokine profile that are activated. Immunological mechanism of occupational asthma may have distinctive pathways with IgE dependent mechanisms and cellular immune IgE non-dependent mechanisms, although most of the inducing agents are called immunogens, allergens or irritants.