nemoci-sympt/PLICNI/sarkoidoza/patofyziologie

CD39 Treg. cells

• Greater proportions of activated CD39+ Treg to CD39- Teff (effector T) cells in patients with sarcoidosis
• Compared with healthy controls (unpublished data). [3]
• These cells do not completely suppress the production of proinflammatory cytokines such as
• IFN-gamma and TNF-alpha at the disease site
• Therefore sarcoid granulomas can still develop [3]

Chemokines mediated by CXCR3

• Associated only with early stages of pulmonary sarcoidosis
• CCL2 and CCL5
• Transition from type 1 to type 2 immune responses [3]
• Elevated in BAL fluid of pulmonary sarcoidosis compared with healthy controls
• Elevated in all stages of pulmonary sarcoidosis
• Continuum of early inflammatory to late fibrotic sarcoidosis [3]

CCL15

• Member of the macrophage inflammatory protein-1 family of chemokines
• Elevated in the BAL fluid of patients with sarcoidosis at radiological stage III
• Associated with 2 year disease outcome
• May be a marker of progressive sarcoidosis [3]

CCL16

• Chemoattractant for lymphocytes and monocytes
• Macrophages, in response to CCL16, increase their production of
• IL-12,
• IL-1beta,
• CCL2,
• TNF-alpha
• protein expression levels elevated in patients with sarcoidosis
• Regardless of clinical phenotype [3]
• Role in amplifying the inflammatory process [3]

CCL18

• Upregulates collagen production by pulmonary fibroblasts
• Increases macrophage secretion of CCL18
• Positive feedback loop leading to pulmonary fibrosis [3]
• Secreted in high quantities by sarcoid macrophages [3]

Dendritic cells

• Identified to have an important role in the pathogenesis of sarcoidosis
• Dendritic cells may be divided into cell subtypes:
• Plasmacytoid
• Myeloid

Plasmacytoid dendritic cells

• Part of the innate immune system
• Expressing a variety of Toll-like receptors
• Secreting large amounts of IFN-alpha following Toll-like receptor-mediated stimulation

Plasmacytoid dendritic cells

• Do not appear to play a large role in sarcoid immunopathogenesis
• Similar numbers in BAL fluid of patients compared with healthy controls

• Reduced dendritic cell function in sarcoidosis peripheral blood
• Compared with that in healthy control subjects

• Phenotypically immature, anergic myeloid dendritic cells
• Increased in sarcoidosis BAL fluid and cutaneous lesions
• Mature dendritic cells
• Located in disease sites in lymph nodes
• Polarize the TH1 T-cells to lymph nodes

Granulomas

• Formed by an interaction between
• Antigen presenting cells (APC)
• Activated T-lymphocytes
• Mainly CD4+ T cells [6]
• This leads to a release of cytokines
• IL-2
• IFN-gamma [6]
• Triggering macrophages to produce
• TNF-alpha
• Strengthen the local inflammation response [6]
• Large numbers of B-lymphocytes were found in intergranulomatous areas of lymph nodes in sarcoidosis patients
• Role of the B-lymphocyte in sarcoidosis remains open
• B-lymphocytes are responsible for the humoral response - antibodies [6]

• TNF-alpha stimulates the
• Differentiation of monocytes into macrophages
• Differentiation of macrophages into epithelioid cells
• Where after giant cells are produced
• Because of the junction of epithelioid cells [6]

• Ultimately, damage to lung tissue and other organs is due to the mass affect of granulomas.
• Granulomas can resolve spontaneously.
• Resolution can be complete, leave an insignificant fibrous scar, or when there is chronic sarcoidosis activity, can cause more extensive tissue damage.
• This occurs when fibroblasts proliferate and produce collagen.
• Granulomas become enclosed and later replaced by collageous fibrous tissue [10]

Macrophage stimulating protein

• Initiates and regulates immune responses
• Differentially expressed between acute and chronic sarcoidosis
• Induce IL-1beta and TNF-alpha production in alveolar macrophages of patients with sarcoidosis
• In radiological stage III [3]
• May propagate the inflammatory process in sarcoidosis [3]

Programmed T-cell death inhibited

• By oncogene products, including the
• Bcl-2 family of genes, which, like Fas, is also highly expressed by T-lymphocytes surrounding granulomatous lesions in sarcoidosis [3]

TH1 cytokines

• Inhibit fibrosis
• Promote granulomatous inflammation [3]

TH2 cytokines

• Promote healing or progressive fibrosis [3]

TNF-alpha

• Pivotal role in the formation and maintenance of sarcoid granulomas
• Produced by
• Pulmonary epithelial cells
• Activated macrophages
• T-cells [3]
• Found to be higher in patients with sarcoidosis with active disease
• Than in those with stable disease
• Use as a prognostic marker [3]
• TNF-alpha release is strongly associated with the pathogenesis of sarcoidosis
• Multiple studies indicating that TNF release is upregulated in BAL cells from patients with active sarcoidosis
• TNF release appears to be compartmentalized
• Increased release in BAL cells
• But almost no release by peripheral blood cells from the same patient [3]

TNF receptor

• Increased expression of members of the TNF receptor superfamilies and related molecules, including
• Fas (CD95)/Fas ligand (FasL) system
• Regulate cell survival and death of T-cells [3]
• Dysregulation of T-cell apoptotic mechanisms may explain the
• Absence of apoptosis in the sarcoid granuloma
• Persistence of inflammation [3]

Th1 x Th2

• The processed antigen is presented by HLA molecules on antigen-presenting cells
• To sarcoid antigen-specific T cells
• Which express restricted Va and Vb regions of the T cell receptor
• Ligation of co-stimulatory signals such as CD80 and CD86 on the APC binding to CD28 on the T cell is required for full T cell activation.
• This leads to release of a variety of cytokines and chemokines activating CD4? T cells
• To become active TH1 cells
• That secrete IL-2 and IFN-g [4]
• That drives granulomatous inflammation yet promotes resolution
• Contributions of TH2 cells + macrophage-derived cytokines, namely TGF-b [4]
• Lead to development of fibrosis and chronic disease !!

Takže by pomohlo více stimulovat Th1 odpověď a inhibovat Th2 odpověď ? Dalo by se cíleně inhibovat migrace a aktivita makrofágů v místě zánětu ?

• Antigenic peptide is presented to the T cell receptor on naive T cells
• Via human leucocyte antigen class II molecules on antigen-presenting cells
• Resulting in activation with subsequent clonal proliferation and T helper (Th)1 polarisation
• With release of cytokines and chemokines [4]
• Th1 cells and macrophages stimulate monocytes to form non-caseating granulomas
• Which may persist or regress [4]
• Fibrosis is an alternative outcome through a transition from a Th1 to a Th2 cytokine profile
• With Th1 cytokines being important in promoting granulomatous inflammation and inhibiting fibrosis [4]

Takže mne třeba napadá zákaz očkování, které by podporovalo tvorbu protilátek a reakce typu Th2... a také vhodnost vyhýbání se infekcím, které by vyžadovaly vyhojení cestou protilátek... jestli je to vůbec možné. Naopak podpořit dozničení toho, co se zničit má a o co už se tělo začalo snažit cestou Th1, jen mu to nešlo....tedy obzvláště pokud by ve hře byla nějaká infekce.

• Healthy controls
• CD4?:CD8?T cell ratios of 2:1
• Most patients with sarcoidosis
• Elevated ratios ranging from 3.5:1 to 15:1 at sites of inflammation

• Th1-dominated inflammation at the site of disease
• Associated elsewhere with peripheral immunological anergy
• T cell lymphopenia
• Reduced delayed-type hypersensitivity to common recall antigens
• May be explained by
• Systemic proliferation of T regulatory cells
• Suppress cell-mediated immunity in the periphery but not locally at sites of disease

• Th17 cell responses associated with
• Autoimmunity
• Defence against extracellular pathogens
• Including increased
• Interleukin-17
• Interferon-gamma
• Interleukin-23R expression by CD4? T cells in lung, peripheral blood and lymph node biopsies of patients

Treated sarcoidosis patients

• Spontaneous high release of TNF-alpha in alveolar macrophages compared to a control
• TNF-alpha seems to play a central role in the pathogenesis [6]

HLA II geny

• Presentation of insoluble antigen(s), expressed on HLA class II molecules on the surface of antigen-presenting cells
• Activates CD4+ lymphocytes
• Triggers the sarcoid immune response [3]

Oxidační stres

• Sarcoidosis has been suggested to trigger an oxidative stress response as indicated by an increased activation of NF-kappa B [14]
• Oxidative stress may contribute to cardiac dysfunction in sarcoidosis
• Through increased susceptibility to free radical injury
• Impairment of intracellular calcium transport [14]

Inflammatory process

• Type 1 T helper cell-dominated local inflammation co-existing with T regulatory-induced peripheral anergy [4]

• Largely a T helper-1-driven immune response
• Exaggerated T helper-1 (TH1)-mediated immune response at sites of disease
• Suppressed peripheral blood responses to common recall antigens
• Poor response to vaccinations
• Undegradable MTB antigens (not present in tuberculosis-specific IGRAs) may be pathogenic in sarcoidosis [1]

• Proliferation of CD25brightFOXP3+ regulatory T-cells [3]
• Local sarcoid inflammation arises when a putative antigenic peptide is presented via major histocompatibility complex class II molecules to CD4+ TH1 lymphocytes
• Clonal proliferation of these activated lymphocytes subsequently occurs
• Produces increased amounts of IL-2 and IFN-gamma
• Released are cytokines and chemokines produced by mononuclear phagocytes including
• Tumor necrosis factor-alpha [TNF-alpha]
• IL-6
• IL-12
• IL-18 [3]
• Monocyte chemotactic protein-1 [3]
• Initiate the formation of noncaseating granulomas
• Depending on TH1/TH2 predominance and the local cytokine network
• Results in either resolution or fibrosis [3]