Ferritin in autoimmune diseases

doi:10.1016/j.autrev.2007.01.016

Autoimmunity Reviews

Volume 6, Issue 7, August 2007, Pages 457-463

https://doi.org/10.1016/j.autrev.2007.01.016 Get rights and content

Abstract

Iron, an essential element for many important cellular functions in all living organisms, can catalyze the formation of potentially toxic free radicals. Excessive iron is sequestered by ferritin in a nontoxic and readily available form in a cell. Ferritin is composed of 24 subunits of different proportions of two functionally distinct subunits: ferritin H and L. The expression of ferritin is under delicate control and is regulated at both the transcriptional and post-transcriptional levels by iron, cytokines, hormones, and oxidative stress. Mutations in the ferritin gene cause the hereditary hyperferritinemia-cataract syndrome and neuroferritinopathy. Hyperferritinemia is associated with inflammation, infections, and malignancies. While elevated levels of ferritin are characteristic of adult-onset Still's disease and hemophagocytic syndrome, both associated with inflammation, it has scantly been evaluated in other autoimmune diseases. In this review, we describe ferritin structure and function, hyperferritinemia in disease states and in autoimmune diseases.

Introduction

Ferritin is nature's unique and conserved approach to controlled, safe use of iron and oxygen, with protein synthesis in animals adjusted by dual, genetic DNA and mRNA sequences that selectively respond to iron or oxidant signals and link ferritin to proteins of iron, oxygen and antioxidant metabolism [1], [2], [3].

It is well established that elevated ferritin levels are found in adult Still's disease, but hyperferritinemia has been scantly investigated in other autoimmune diseases. The rationale for evaluating this protein in autoimmune diseases derives from it being an acute phase reactant (APR), and hence increased during inflammation. APRs have been found to be elevated and conducive of activity of disease, such as C-reactive protein (CRP) in rheumatoid arthritis. In SLE, other than an elevated erythrocyte sedimentation rate (ESR), APRs such as serum amyloid component P (SAP), C-reactive protein (CRP), and mannose binding lectin (MBL) are not raised, indicating a possible mechanism of antibody production that blocks their function. To investigate this hypothesis, we have previously described elevated titers of anti-SAP antibodies in 44% of 328 SLE patients that correlated with disease activity [4]. In this review we discuss ferritin and its function, altered states of ferritin leading to disease, and hyperferritinemia reported in various autoimmune diseases.

Section snippets

Ferritin structure

Ferritin is the major intracellular iron storage protein in all organisms. Ferritins share a unique protein cage structure that resembling spherical viruses that are preserved throughout species and permit storage of up to 4500 Fe (III) atoms. Polypeptide subunits of ferritin spontaneously fold into 4 helix bundles and assemble into hollow spheres with inner cavities, depending on whether there are 12 (mini-ferritins) or 24 (maxi-ferritins) subunits. When there are mini-ferritins, such as in

Ferritin regulation and function

Controlling iron/oxygen chemistry in biology depends on multiple genes, regulatory messenger RNA (mRNA) structures, signaling pathways and protein catalysts. Ferritin, a protein nanocage around an iron/oxy mineral, centralizes the control. Complementary DNA (antioxidant responsive element–/Maf recognition element—ARE/MARE) and mRNA (iron responsive element—IRE) responses regulate ferritin synthesis rates. Maxi-ferritins concentrate iron for the bio-synthesis of iron/heme proteins, trapping

Ferritin and inflammation/infection

Macrophage ferritin accumulates during inflammation, when serum iron decreases and iron in specific cells increases, leading to ferritin with more iron/protein cage. Pathogen ferritins are the mini-ferritins that protect bacterial DNA when exposed to ferrous ions and hydrogen peroxide in vitro and confer cellular resistance to oxidative damage in vivo. During infection or inflammation, it is the relative “iron deficiency” created by the host redistribution of iron, with a deficit in serum and

Ferritin and the immune system

Ferritin has been reported to exhibit different immunological activities including: binding to T lymphocytes and inhibition of E-rosette formation, a concanavalin A response [6], a source for iron to catalyze oxygen radicals in the Haber–Weiss reaction, suppression of the delayed type of hypersensitivity to induce anergy [7], suppression of antibody production by B lymphocytes [8], decreasing the phagocytosis of granulocytes [9], and regulating granulomonocytopoiesis [9].

Altered ferritin levels and disease

Ferritin and iron homeostasis have been implicated in the pathogenesis of many diseases, including diseases involved in iron acquisition, transport and storage (primary hemochromatosis) as well as in atherosclerosis [5], Parkinson's disease [10], Alzheimer disease [11], and pulmonary disease [12]. Genetic mutations of the ferritin IRE region as well as coding regions of ferritin cause some hereditary human diseases. Ferritin L IRE mutations cause the hereditary hyperferritinemia-cataract

Ferritin and malignancies

Early views of the relationship between ferritin and cancer stem from work demonstrating an increase in total ferritin as well as a shift toward acidic (H-rich) ferritins in the serum of patients with various malignancies. However, subsequent evaluations of ferritin levels in tumor tissue itself have revealed a complex, perhaps disease-specific picture: for example, in some cases such as colon cancer, testicular seminoma, and breast cancer, increases in ferritin in tumor tissue versus

Hyperferritinemia in autoimmune diseases

Adult onset Still's disease (AOSD) is a systemic inflammatory disorder characterized by fever, arthritis, rash, and hyperferritinemia in 89% of cases [17]. Overproduction of IL-18 may contribute to the pathogenic mechanism of AOSD, and serum sIL-2R levels may be used as a marker for monitoring disease activity in AOSD [18]. Reactive hemophagocytic syndrome is not uncommon in AOSD and should be sought in a patient with AOSD with extremely elevated serum ferritin and triglyceride levels [19], [20]

Conclusions

Perturbations in ferritin function are not only detrimental for iron homeostasis, but can lead to disease states by mechanisms of inflammation, infection, injury, and repair. Ferritin has been implicate in various diseases and may be important in autoimmune conditions. Hyperferritinemia is present in active SLE, RA, and may play a role in MS. Further investigation into the mechanisms of ferritin in this group of diseases is warranted.

Take-home messages

•
Controlling iron/oxygen chemistry in biology depends on multiple genes, regulatory messenger RNA (mRNA) structures, signaling pathways and protein catalysts.
•
Ferritin synthesis is regulated by cytokines (TNFα and IL-1α) at various levels (transcriptional, post-transcriptional, and translational) during development, cellular differentiation, proliferation, and inflammation. The cellular response by cytokines to infection stimulates the expression of ferritin genes.
•
Ferritin has been reported to

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Citation Excerpt :
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¹: Incumbent of the Laura Schwartz-Kipp Chair for Autoimmune Diseases, Tel-Aviv University, Israel.

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Ferritin in autoimmune diseases

Abstract

Introduction

Section snippets

Ferritin structure

Ferritin regulation and function

Ferritin and inflammation/infection

Ferritin and the immune system

Altered ferritin levels and disease

Ferritin and malignancies

Hyperferritinemia in autoimmune diseases

Conclusions

Take-home messages

Blood

Clin Chim Acta

Blood

J Inorg Biochem

Neurosci Lett

Free Radic Biol Med

Atherosclerosis

J Neurol Sci

Brain Res

Metabolism

Cellular regulation and molecular interactions of the ferritins

Cell Mol Life Sci

Iron metabolism and the IRE/IRP regulatory system: an update

Ann NY Acad Sci

Anti-serum amyloid component P antibodies in patients with systemic lupus erythematosus correlate with disease activity

Ann Rheum Dis

Elevation of serum ferritin levels as a marker for active systemic lupus erythematosus

Clin Exp Rheumatol

Effects of isoferritins on human granulocytes

Cancer

Identification of leukemia-associated inhibitory activity as acidic isoferritins. A regulatory role for acidic isoferritins in the production of granulocytes and macrophages

J Exp Med

Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinemia and cataract

Nat Genet

Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease

Nat Genet