6/8/20

Kebutuhan Nutrisi Ibu Hamil Di

Era Pandemi Covid-19
Noroyono Wibowo

Masalah Covid-19
• Diagnostik: belum ada kesepakatan resmi
• Batasan Self limiting diseases?
• Antigen neutralisasi?

1

No. of samples positive for SARS-CoV-2 by RT-PCR/ total no. of samples in aggregated studies (%)
Nasopharyngeal swabs: 31/35
(88.6%)
Zou L et al, NEJM, 2020
Kujawski et al, medRxiv, 2020
Chan JF et al, Lancet
Stool: 34/48 (70.8%)
Anal swabs: 16/78 (20.5%)
Rectal swabs: 4/23 (17.4%)
Cui P et al, medRxiv, 2020
Chen W et al, Emerg Microbes Infect
Pan Yet al, Lancet Infect Dis, 2020
To KKW et al, Lancet Infect Dis, 2020
Kujawski et al, medRxiv, 2020
Xie C et al, UID, 2020
Young BE et al, JAMA, 2020
Zhang L et al, IMV, 2020
COVID-19 Shedding
Conjunctival swabs: 2/188
(1.1%)
Xu L et al, medRxiv, 2020
Zhang X et al, medRxiv, 2020
Sun X et al, medRxiv, 2020
Urine: 0/76 (0%)
Pan Yet al, Lancet Infect Dis, 2020
To KKW et al, Lancet Infect Dis, 2020
Kujawski et al, medRxiv, 2020
Xie C et al, UID, 2020
Young BE et al, JAMA, 2020
Wolfel R et al medRxiv, 2020
Sputum: 48/49
(97.9%)
Pan Y et al, Lancet Infect Dis, 2020
Kujawski et al, medRxiv, 2020
Chen L et al, Am J Gastroenterol, 2020
Lin C et al, medRxiv, 2020
Chan JF et al, Lancet, 2020
Blood:20/162 (12.3%)
Chen W et al, Emerg Microbes Infect, 2020
To KKW et al, Lancet Infect Dis, 2020
Kujawski et al, medRxiv, 2020
Xie C et al, UID, 2020
Young BE et al, JAMA, 2020
Chan JF et al, Lancet, 2020
Wolfel R et al medRxiv, 2020
6/8/20
Throat swabs: 45/75 (60%)
Post. Throat saliva: 31/35 (88.6%)
Oral swabs: 7/15 (46.7%)
Pan Y et al, Lancet Infect Dis, 2020
Zou L et al, NEJM, 2020
Kujawski et al, medRxiv, 2020
Chen L et al, Am J Gastroenterol, 2020
Lin C et al, medRxiv, 2020
To KKW et al, Lancet Infect Dis, 2020
To KKW et al, Clin Infect Dis, 2020
Chan JF et al, Lancet, 2020
Vaginal swabs: 0/35 (0%)
Cui P et al medRxiv, 2020
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Contagion

Contagious
No 0%
symptoms 30% No symptoms IMMUNE

Contagious
0%
Mild/moderate Mild/moderate
The whole symptoms 55% No symptoms
symptoms IMMUNE
population
Death
(100%) rates
Contagious
Severe 15%
symptoms 10% No symptoms Severe
symptoms Hospitalization IMMUNE

Contagious
50%
Critical
symptoms 5% No symptoms Severe
symptoms
ICU/Ventilation IMMUNE

Dead
Days 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

References:
1. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Lauer SA et al. Ann Intern Med. 2020
Mar 10.
2. Impact of non-pharmaceutical interventions (NPIs) to reduce COVID19 mortality and healthcare demand. Neil M Ferguson et al. Imperial College COVID-19 Response Team.
16 March 2020.
3. Viral dynamics in mild and severe cases of Covid-19. Yang Liu et al. The Lancet, March 19, 2020.

Algorithm Implementation
Countries Experience

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Unclear
Mechanism
of Disease

Different Diagnostic
target of tool under
Gene develop
High potencial
False Negative Common problem
in diagnostics new
High potencial disease outbreak
False Positive
Not yet Lack of
standardize standardization
method of sampel type
Unclear
Sampling,
storage,
handling sample
Protocol

Physiological Changes:
1. Anatomical structure of the respiratory system
2. Reproductive endocrine
3. Immune responses

Higher risk of serious illness and death from

viral infections during pandemics such as
influenza (2x non pregnant), SARS (30%
maternal mortality) and ebola

Higher risk of miscarriage, preterm

delivery, preeclampsia

COVID-19 and pregnancy?

European Journal of Clinical Microbiology & Infectious Diseases

https://doi.org/10.1007/s10096-020-03897-6

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• Pregnancy itself alters the body’s immune system and response to viral infections
in general, which can occasionally cause more severe symptoms. This may be the
same for COVID-19.
• But there is currently no evidence that pregnant women are more likely to be
severely unwell needing admission to intensive care or die from the illness than
non-pregnant adults.

Coronavirus (Covid-19) infection in pregnancy. RCOG. 4 June 2020

Changes in respiratory system

• Diaphragm will move up
• The subcostal angle and
transverse diameter of
the thoracic cavity will
increase further in the
third trimester.
Decreased compliance of chest
wall, eventually lead to a 20 to Increased tidal volume
Prone hypoxia
30% reduction in functional and hyperventilation
residual capacity (FRC)

• CD3 + CD4 + and CD8 + T cells in the blood decreased

Changes in the immune system • Decreased number and activity in NK cells and T cells

High expression of ACE2 in pregnant women

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Universal Screening for SARS-CoV-2 in Women Admitted for Delivery

Asymptomatic, Symptomatic,
SARS-CoV-2- SARS-CoV-2-
positive, positive,
13.50% 1.90%

SARS-CoV-2-
negative,
84.60%

Symptom Status and SARS-CoV-2 Test Results among 215 Obstetrical

Patients Presenting for Delivery. DOI: 10.1056/NEJMc2009316

https://doi.org/10.1016/j.ejogrb.2020.04.006

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Evidence
• 43 pregnant women +ve SARS-CoV-2: 86% mild, 9% severe, and 5% critical
(similar pattern of disease severity to non-pregnant adults
• 215 women in labour and birth unit: 13% +ve, 12% with symptoms, 88%
asymptomatic
• UKOSS: 427 pregnant women admitted with confirmed SARS-CoV-2
• 9% required level-3 critical care
• <1% received ECMO
• 1% died

Coronavirus (Covid-19) infection in pregnancy. RCOG. 4 June 2020

Pathogens, allergens, self-antigens

Maternal
Immune System
­ Anti-inflammatory
factors
¯ Proinflammatory
factors Anti-inflammatory
IL-4 IL-12

IL-10 IL-2
Proinflammatory
Fetoplacental TGF-b IFN-g
tissues/Pregnancy
PIBF TNF-a
associated horm ones
Tolerogenic DCs NK cells
HORMONE LEVELS

M2 Macrophages M1 Macrophages

Th2 Cells Th1 Cells

Regulatory T cells Th17 Cells

Antibody Estradiol
Estriol
­Successful Pregnancy Progesterone
¯ Susceptibility to Inflammatory Diseases
­ Susceptibility to Infectious Diseases

First Second Third

Hormonal changes and exposure to fetal antigens during pregnancy
skew the maternal immune system toward higher anti-inflammatory
responses and away from proinflammatory responses, especially during
the third trimester. These immunological changes are necessary for
successful pregnancy, but also affect the outcome of disease.
TRIMESTER
During the three trimesters of pregnancy, there is a shift in the balance of proinflammatory and
anti-inflammatory responses. By the third trimester, anti-inflammatory responses, including the
activity of M2 macrophages, Th2 cells, and regulatory T cells, are elevated and inflammatory
responses, including the activity of NK cells, M1 macrophages, and Th1 cells, are reduced.
Changes in the concentrations of sex steroids, including estradiol, estriol, and progesterone, lead
to the immunological shifts during pregnancy.

Horm Behav. 2012 August ; 62(3): 263–271. doi:10.1016/j.yhbeh.2012.02.023.

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Pregnancy and pregnancy-associated hormones alter immune responses and

disease pathogenesis

• Inflammatory responses are lower and anti-inflammatory responses are higher during pregnancy
• The immunological shift during pregnancy promotes healthy fetal development
• The severity of diseases that are caused by inflammation is reduced during pregnancy
• The severity of diseases mitigated by inflammatory responses is increased during pregnancy
• Sex steroids mediate the immunological shift and altered disease pathogenesis during pregnancy

Horm Behav. 2012 August ; 62(3): 263–271. doi:10.1016/j.yhbeh.2012.02.023.

List of key selected genes that are regulated by estrogen in cells of innate and adaptive immune system.

immune cell List of genes

Neutrophil CINC-1, CINC-2β, • Hsu JT, Kan WH, Hsieh CH, Choudhry MA, Schwacha MG, Bland KI, et al. Mechanism of estrogen-mediated attenuation of hepatic injury following trauma-hemorrhage: Akt-dependent HO-1 up-regulation. J Leukoc Biol (2007)
82(4):1019–26. doi:10.1189/jlb.0607355
CINC-3, TNFα, IL-6, IL- • Yu HP, Hsieh YC, Suzuki T, Choudhry MA, Schwacha MG, Bland KI, et al. Mechanism of the nongenomic effects of estrogen on intestinal myeloperoxidase activity following trauma-hemorrhage: up-regulation of the PI-3K/Akt pathway. J
1β Leukoc Biol (2007) 82(3):774–80. doi:10.1189/ jlb.0307182
• Cuzzocrea S, Genovese T, Mazzon E, Esposito E, Di Paola R, Muia C, et al. Effect of 17beta-estradiol on signal transduction pathways and secondary damage in experimental spinal cord trauma. Shock (2008) 29(3):362–71.
doi:10.1097/SHK.0b013e31814545dc

Macrophage iNOS, NO, IL-6, TNFα • Cutolo M, Sulli A, Capellino S, Villaggio B, Montagna P, Seriolo B, et al. Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus (2004) 13(9):635–8. doi:10.1191/0961203304lu1094oa
• Karpuzoglu E, Ansar Ahmed S. Estrogen regulation of nitric oxide and inducible nitric oxide synthase (iNOS) in immune cells: implications for immunity, autoimmune diseases, and apoptosis. Nitric Oxide (2006) 15(3):177–86.
doi:10.1016/j.niox.2006.03.009
• Dai R, Phillips RA, Zhang Y, Khan D, Crasta O, Ansar Ahmed S. Suppression of LPS-induced Interferon-gamma and nitric oxide in splenic lymphocytes by select estrogen-regulated microRNAs: a novel mechanism of immune mod-
ulation. Blood (2008) 112(12):4591–7. doi:10.1182/blood-2007-10-116376
• Hsieh CH, Nickel EA, Chen J, Schwacha MG, Choudhry MA, Bland KI, et al. Mechanism of the salutary effects of estrogen on kupffer cell phago- cytic capacity following trauma-hemorrhage: pivotal role of Akt activation. J Immunol (2009)
182(7):4406–14. doi:10.4049/jimmunol.0803423
• Karpuzoglu E, Phillips RA, Dai R, Graniello C, Gogal RM Jr, Ansar Ahmed S. Signal transducer and activation of transcription (STAT) 4beta, a shorter isoform of interleukin-12-induced STAT4, is preferentially activated by estrogen.
Endocrinology (2009) 150(3):1310–20. doi:10.1210/en.2008-0832

•
Dendritic IL-6, IL-10, CXCL8, •
Liu HY, Buenafe AC, Matejuk A, Ito A, Zamora A, Dwyer J, et al. Estrogen inhibition of EAE involves effects on dendritic cell function. J Neurosci Res (2002) 70(2):238–48. doi:10.1002/jnr.10454
Bachy V, Williams DJ, Ibrahim MA. Altered dendritic cell function in normal pregnancy. J Reprod Immunol (2008) 78(1):11–21. doi:10.1016/j. jri.2007.09.004
cells CCL2, TGFβ, IL-23, IL- • Papenfuss TL, Powell ND, McClain MA, Bedarf A, Singh A, Gienapp IE, et al. Estriol generates tolerogenic dendritic cells in vivo that protect against autoimmunity. JImmunol (2011) 186(6):3346–55. doi:10.4049/ jimmunol.1001322
12
•
Th1 IFNγ •
Grasso G, Muscettola M. The influence of beta-estradiol and progesterone on interferon gamma production in vitro. Int J Neurosci (1990) 51(3–4):315–7. doi:10.3109/00207459008999730
Fox HS, Bond BL, Parslow TG. Estrogen regulates the IFN-gamma promoter. J Immunol (1991) 146(12):4362–7.
• Karpuzoglu-Sahin E, Hissong BD, Ansar Ahmed S. Interferon-gamma levels are upregulated by 17-beta-estradiol and diethylstilbestrol. J Reprod Immunol (2001) 52(1–2):113–27. doi:10.1016/S0165-0378(01)00117-6

Th2 IL-4 • Lambert KC, Curran EM, Judy BM, Milligan GN, Lubahn DB, Estes DM. Estrogen receptor alpha (ERalpha) deficiency in macrophages results in increased stimulation of CD4+ T cells while 17beta-estradiol acts through ERalpha to
increase IL-4 and GATA-3 expression in CD4+ T cells indepen- dent of antigen presentation. J Immunol (2005) 175(9):5716–23. doi:10.4049/ jimmunol.175.9.5716

Tregs FoxP3, PD-1, CTLA-4 • Polanczyk MJ, Carson BD, Subramanian S, Afentoulis M, Vandenbark AA, Ziegler SF, et al. Cutting edge: estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment. JImmunol (2004) 173(4):2227–30.
doi:10.4049/jimmunol.173.4.2227
Polanczyk MJ, Hopke C, Huan J, Vandenbark AA, Offner H. Enhanced FoxP3 expression and Treg cell function in pregnant and estro- gen-treated mice. J Neuroimmunol (2005) 170(1–2):85–92. doi:10.1016/j. jneuroim.2005.08.023
• Polanczyk MJ, Hopke C, Vandenbark AA, Offner H. Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1). Int Immunol (2007) 19(3):337–43. doi:10.1093/intimm/dxl151
Tai P, Wang J, Jin H, Song X, Yan J, Kang Y, et al. Induction of regulatory T cells by physiological level estrogen. J Cell Physiol (2008) 214(2):456–64. doi:10.1002/jcp.21221

B cells Immunoglobulin, • Grimaldi CM, Cleary J, Dagtas AS, Moussai D, Diamond B. Estrogen alters thresholds for B cell apoptosis and activation. J Clin Invest (2002) 109(12):1625–33. doi:10.1172/JCI0214873

CD22, SHP-1, Bcl-2,

VCAM-1

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IAV infection
AREG

P4 P4 Proliferation
PR
PR

PR
Proliferation
P4 P4
PR
PR

Th17
TGF-b
Progesterone
O
IL-6 H AREG Amphiregulin
Naive CD39 H
IL-22
T cell
O
H
H Repair
Inflammatory and Anti-Inflammatory
O
virus clearance H
H
H
H
O

+ Progesterone
Alveoli

Progesterone (P4) reduces inflammation and promotes repair of the respiratory epithelium to protect
against influenza A virus (IAV) infection.

MucosalImmunology | VOLUME 10 NUMBER 5 | SEPTEMBER 2017. doi:10.1038/mi.2017.35

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Sex differences in innate immune responses during the effector and repair phases of respiratory virus infection
Proinflammatory / Effector Phase Regulatory/Repair phase

IFNa ­ Increased in Females or by E2/ER signaling

IL-8, IL-12, IL-1b ­ IFNg ­

CCL2 ­
M2 polarization
Numbers­
Migration­ TLRs­
­ Differentiation Degranulation ­ M2 polarization
Phagocytosis ­
CCL2 ­ Numbers­
IL-5/IL-13 in
IL-6, TNFa ­ Survival­ Lung inflammation ­

IL-10 ­ ? Numbers­
Regulated by A/AR
neutrophil ­
signaling ¯
Precursors ­
­ Differentiation
TNFa ­
M1 polarization ?
Numbers­
activity­
Numbers­
TNFa , IL-6, IL-1b­
Increased in males or by A/AR signaling
Front. Immunol. 9:1653. doi: 10.3389/fimmu.2018.01653

at term, daily some

150,000 syncytial
‘knots’ disseminate to
the lung to be
destroyed there

1.Benirschke K, Kaufmann P. Baergen RN Pathology

2.of the Human Placenta. Ed. 5, Springer-Verlag NY
3.2006; 81.

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Responses of endothelial cells following phagocytosis of apoptotic or necrotic trophoblast debris.

Apoptotic trophoblast debris Necrotic trophoblast debris

Protection against activation by chemical or Increased endothelial cell surface ICAM-1,E-selectin
biological activators. • Abumaree MH, Chamley LW, Badri M, El-Muzaini MF. Trophoblast debris
modulates the expression of immune proteins in macrophages: a key to
• Abumaree MH, Stone PR, Chamley LW. The effects of apoptotic, deported
maternal tolerance of the fetal allograft? J Reprod Immunol 2012;94(2):
human placental trophoblast on macrophages: possible consequences for
pregnancy. J Reprod Immunol 2006;72(1e2):33e45. 131e41.
• Schmorl G. Pathologisch-anatomische untersuchungen uber puerperal-
eklampsie. Leipzig: Verlag von FC Vogel; 1893. p. 104.

Increased monocyte adhesion to endothelial cells,

Increased secretion of IL-6, TGFb1
• Abumaree MH, Chamley LW, Badri M, El-Muzaini MF. Trophoblast debris
modulates the expression of immune proteins in macrophages: a key to
maternal tolerance of the fetal allograft? J Reprod Immunol 2012;94(2):
131e41.
• Chen Q, Stone P, Ching LM, Chamley L. A role for interleukin-6 in
spreading endothelial cell activation after phagocytosis of necrotic
trophoblastic mate- rial: implications for the pathogenesis of pre-
eclampsia. J Pathol 2009;217(1): 122e30.
• Schmorl G. Pathologisch-anatomische untersuchungen uber puerperal-
eklampsie. Leipzig: Verlag von FC Vogel; 1893. p. 104.

Malnutritional statuses as virulence factor for the SARS-CoV-2

Hyponutrition Respiratory droplets Hypernutrition

from infected person
Mainly protein- Mainly sarcopenic
in close contact.
energy malnutrition obesity

Conditions possibly associated Conditions possibly associated

with increased viruslence with increased virulence
Shortage diseases Wellness diseases
Low body proteins (low intake) Low body proteins (high sedentary)
Contaminated body
Low immunoreactivity parts, objects, Low-grade inflammation
Reduced T cell function surfaces Increased immunoreactivity
Increased IL-4 and IL-10 Exhaustion of T cells
Vitamin A, D, and E deficiencies Most relevants virulence co-factor Reduced IL-4 and IL-10
Vitamin B deficiencies Immune dysfunction (chronic - e.g., organ transplant, Vitamin A, D, and E deficiency
cancer-or transient - e.g., athlete after training -)
Iron-deficiency anemia Vitamin B deficiencies
Micronutrient deficiencies Increased susceptibility Iron, zinc, and selenium deficiencies
Older age, comorbid conditions,
polypharmacotherapy The nutritional implications that may
The structure of SARS-CoV-2 experience patients with SARS-CoV-2
War sites Symptom/sign Nutritional effect
Spike (S) Lungs, but also brain, liver, kidney, and gut High body temperature Increased energy needs
Envelope (E) Tachypnea Increased energy expenditure
Cytokine storm Loss of body constituents
Membrane (M) Diarrhea Malabasorption
Abdominal pain Lack of appetite
Nucleocapsid (N) Lethargy, anorexia Reduced food supply
RNA genome Social isolation Reduced food security
Mental distress Lack of desire to feed
Reduced movement Loss of lean mass
Front. Med. 7:146. doi: 10.3389/fmed.2020.00146

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LAYERS OF THE IMMUNE SYSTEM TYPES OF IMMUNITY

Physical and blochemical barriers Innate immune system

Physical barriers: e.g. skin, gastrointestinal tract (including Non-spesific and fast (minutes or hours)
interactions between the gut lining and gut microbiota), respiratory
Physical barriers
tract, nasopharynx, cilia, eyelashes, other body hair
Blochemical mechanisms
Biochemical mechanisms: e.g. secretions, mucus, bile, gastric acid,
saliva, tears, sweat Inflammatory response
General immune responses: inflammation, antimicrobial Complement system
substances, non-spesific cellular responses Phagocytes (e.g. neutrophils, macrophages)
Complement system – opsonization, chemotaxis, cell lysis,
agglutination
Adaptive (acquired) immune system
Highly spesific and slow (days)
Immune cells
B cells – humoral, antibody-driven adaptive immunity
Leukocytes – monocytes, neutrophils, eosinophils, basophils,
lymphocytes T cells – cell-mediated, cytotoxic adaptive immunity
Granulocytes – neutrophils, eosinophils, basophils T cells receptors only recognize antigens bound to certain receptor
molecules (MHC I or II)
Lymphocytes – B cells, T cells (cytotoxic, helper (e.g. Th1, Th2,
TH17), memory, regulatory), natural killer cells T helper and cytotoxic T cells contribute to T cell recognition and
activation by binding to either MHC I or II
Phagocytes – neutrophils, monocytes, macrophages, mast cells,
dendritic cells Immunoglobulins
Cell surface proteins: MHC I or II

Antibodies
Immunoglobulins – IgA, IgD, IgE, IgG, IgM

Micronutrients
Vitamins: A, D, C, E, B6, B12 dan B9 (folate), Minerals: zinc, iron, selenium, magnesium

Contribute to integrity
Vitam ins A, D, C, E, B6, B12,
1. Physical barriers folate, iron, Zn
(e.g. skin, GI and respiratory tracts)

Regulation of
2. Innate im m une 4. Adaptive im m une
3. Inflam m atory response inflam m ation
response response
Vitam in A, C, E, T cell proliferation
Oxidative B6, Zn, Fe, Cu, differentiation &
2 (A). Cellular response burst & self- • Bridges the gap when innate response Se, M g 4. Antigen presentation function
• Phagocytes identify pathogens (e.g. via TLRs) then kill protection can no longer cope and the adaptive response • Spesific im m une response when innate im m unity and inflam m ation can noVitam in A, D, C, E,
and digest them Vitam in C & E, is just starting longer cope with infection B6, B12, Zn, Fe, Cu,
- Digested protein antigens are presented to adaptive Fe, Zn, Cu, Se, • Triggered by innate im m une cells, proinflam m atory - dendritic cells present antigens to naïve T helper cells via M HC-II Se
system via M HCs; only then will T cells react Mg cytokines (e.g. Ils, TNF- a , ifn g , GM -CSF) and com plexes
com plem ent - Naive T helper cells are fully activated after second signal from APCs
- Proinflam m atory cytokines are released, initiating
inflam m atory response • Causes vasodilation, increased vascular perm eability, - Likelihood of T helper cell activation increased by inflam m atory
release of inflam m atory m ediators (e.g. bradykinins, response
• NK cells inject cytotoxic substances iinto pathogens prostaglandins), neutrophil chem otaxis, m icrovascular
• Neutrophils and other phagocytes are triggered and coagulation, fever, raised inflam m atory m arkers (e.g. • T helper cells then differentiate to:
- TH1 cells – prom ote cytotoxic T cells and cell-m ediated im m unity Inhibitory
the pathogen is phagocytosed CRP), and upregulation of costim ulatory m olecules (e.g.
• During this process, ROS and NO are produced in the M HC-II, B7) that encourage activation of adaptive - TH2 cells – prom ote B cells and hum oral im m unity actions
Innate im m une-cell
oxidative (respiratory) burst response Vitam in D, E,
proliferation, B6
differentiation,
function &
2 (B). Biochem ical response m ovem ent
• Com plem ent system is activated, either by: Vitam in A, D, C, E,
4 (A). Hum oral im m unity 4 (B). Cell-m ediated im m unity
- Antibody-antigen (i.e. im m une) com plexes on B6, B12, folate,Zn,
Fe, Cu, Se, M g • TH2 cells activate B cells via M HC II on surface of B cells • TH1 cells active APCs and cytotoxic T cell response
pathogen surfaces
- Activated B cells m ature into plasm a cells and m ake • Im m ature T cells m ust express CD3 and CD4 or CD8 (never both) and blind to M HC
- M annose-binding lectin binding to m annose on antibodies com plexes – those that fail im m unological tolerance (self-tolerance) selection
pathogen surfaces
- Once inferction has cleared, the m ost highly antigen- process are destroyed
- C3, which reacts directly with pathogen surface spesific plasm a cells rem ain as dorm ant m em ory B • Activation of APCs:
• All com plem ent pathways generate enzym e C3 cells - TH1 cells recognize M HC II-restricted antigen on infected APC and activate it
convertase, to cleave C3 - Upon reinfection, im m ediate plasm a cell proliferation
- Once activated, APCs increase production of NO and superoxide radicals –
- C3a augm ents inflam m atory response occurs
optim izes kiling m echanism s and effective destruction of pathogens
- C3b causes opsonization • Antibodies (im m unoglobulins):
• Cytotoxic T-cell responses:
- Neutralize toxins by directly binding to them
- C5b triggers form ation of M AC, resulting in osm otic - Activated APCs present antigen to spesific cytotoxic T cell receptor within M HC I,
lysis - Blind to antigens on pathogen surfaces, triggering along with second signals – aided by IL2, TH1 cells and cytotoxic T cells
agglutinization to im pair m obility and opsonization to
• Antim icrobial substances discourage m icrobial - Activated cytotoxic T cells identity infected cells and destroy them
enhance phagocytosis
growth Antibody - After infection has cleared, the m ost antigen – spesific cytotoxic T
Antim icrobial - Blind to antigens to form com plexes that cells rem ain as dorm ant m em ory T cells Cell-m ediated
- Com plem ent m ainly provides bacterial im m unity production &
activate com plem ent pathway im m unity
- Interferons play a sim ilar role in viral infections activity function - Upon reinfection, any APC (not just dendritic cells) can activate
Vitam in A, D, - Directly activate effectors cells such as cytotoxic T cells directly (faster cell – m ediated im m une Vitam in A, D, C,
• Proinflam m atory cytokines also released, to Vitam in A, D, C,
C, Zn, Fe, Cu, dendritic cells, NK cells, cytotoxic T cells response) E, B6, B12,
m ediate acute inflam m atory response E, B6, B12,
Se folate, Zn, Fe, Cu,
folate, Zn, Fe, Cu,
- Includes Ils, TNFs, chem okines (e.g. M CP-1), IFN g Se
Se, M g

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Potential therapeutic effects of MSCs in respiratory lung

injury are mediated by different mechanisms including but
not limited to secreted paracrine factors, extracellular
vesicles (EVs), and possibly mitochondrial transfer,
promoting tissue protection, immunomodulation, and
possibly viral resistance.

European Respiratory Journal 2020; DOI: 10.1183/13993003.00858-2020

Vitamin A status and mucosal immune system

Vitamin A insufficiency Vitamin A sufficiency

IgA

Mucus Mucus Mucus

Compromised barrier

a4b7+ CCR9+/- a4b7+ CCR9+/- Compensatory increases Bacterial invasion

in aEb7+ Tregs
a4b7+ CCR9+/-
FoxP3 Th1/2/17
IgA + B Decreased homing
of effector cells IgA + B
aEb7+
T-FH RA
FoxP3 Th1 Th17

RA T-FH X Defective IgA

production
naive B
naive B
Mucosal RA
deficiency
APC DCs
naive T RA
naive T RA
Progenitors
ProDCs

Cellular interaction: ISSN 0083-6729, DOI: 10.1016/B978-0-12-386960-9.00004-6

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Retinol
• Vitamin A/retinol also has a direct function in the maintenance of self-renewal and prevention of differentiation
of pluripotent stem cells
• Chen, L.; et al. Suppression of ES cell differentiation by retinol (vitamin A) via the over expression of Nanog. Differentiation 2007, 75, 682–693.
• Chen, L; Khillan, J.S. Promotion of feeder-independent self-renewal of embryonic stem cells by retinol (vitamin A). Stem Cells 2008, 26, 1858–1864.
• Chen, L.; Khillan, J.S. A novel signaling by vitamin a/retinol promotes self-renewal of mouse embryonic stem cells by activating PI3K/Akt signaling pathway via insulin-
like growth factor-1 receptor. Stem Cells 2010, 28, 57–63.
• Zhang, S.; et al. Retinol (vitamin A) maintains self-renewal of pluripotent germline stem cell (mGSCs) form adult mouse testis. J. Cell Biochem. 2011, 112, 1009–1021

• Vitamin A/retinol supports self-renewal of embryonic stem (ESCs) cells by elevating the expression of NANOG
and OCT4, the critical transcription factors for the maintenance of pluripotency of ESCs
• Boiani, M.; Scholer, H.R. Regulatory networks in embryo-derived pluripotent stem cells. Nat. Rev. Mol. Cell Biol. 2005, 6, 872–881.

• Retinol executes its function by activating the phosphatidylinositol 3 (PI3) kinase signaling pathway via insulin
like growth factor 1 (IGF1) receptor
• Chen, L.; Yang, M.; Dawes, J.; Khillan, J.S. Suppression of ES cell differentiation by retinol (vitamin A) via the over expression of Nanog. Differentiation 2007, 75, 682–
693.

• Both mTORC1 and mTORC2 complexes were activated by the retinol signaling

• Contrary to its role in cell differentiation, short term exposure of murine ESCs to retinoic acid during early
differentiation prevents spontaneous differentiation of these cells. The cells retain the capacity to
differentiate into cardiomyocytes, neuronal cells and visceral endoderm, the derivatives of all three germ
layers.
• Wang, R; Liang, J.; Yu, H.-M.; Liang, H.; Shi, Y.-J.; Yang, H.-T. Retinoic acid maintains self-renewal of murine embryonic stem cells via a feedback
mechanism. Differentiation 2008, 76, 931–945.

• Stem cells do not have the capacity to synthesize retinoic acid

• Chen, L; Khillan, J.S. Promotion of feeder-independent self-renewal of embryonic stem cells by retinol (vitamin A). Stem Cells 2008, 26, 1858–1864.

• Neurons in the adult brain which are not directly exposed to blood, depend on retinoic acid for regulating
learning and memory as well as protein translation. The cells that take up vitamin A are cells in the
blood/brain barrier including choroid plexus. These cells express high levels of STRA6 receptor whereas
neurons by themselves do not express genes involved in the vitamin A uptake
• Chen, N.; Onisko, B.; Napoli, J.L. The nuclear transcription factor RARα associates with neuronal RNA granules and suppresses translation. J. Biol.
Chem. 2008, 283, 20841–20847.
• Aoto, J.; Nam, C.I.; Poon, M.M.; Ting, P.; Chen, L. Synaptic signaling by all-trans retinoic acid in homeostatic synaptic plasticity. Neuron 2008, 60,
308–320.

• stem cells in general may not have the capacity to metabolize retinol to retinoic acid
• Jaspal S. Khillan. Vitamin A/Retinol and Maintenance of Pluripotency of Stem Cells Nutrients 2014, 6(3), 1209-1222

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The diverse stages of viral replication cycles that are inhibited by zinc.

Adv Nutr 2019;10:696–710; doi: https://doi.org/10.1093/advances/nmz013.

The proposed protective mechanisms of zinc in COVID-19

Mucociliary
SARS-CoV-2 clearance
replication
Cilia Ciliary beat
m orphology frequency

?
ACE2 6
Zn High COVID-19
Uncoating Protein assem bly
mortality risk factors
Zn Viral RNA
Tight junctions (ZO-1; Claudin-1)

1
2
Translation
RdRp Barrier function
Transcription Ageing (leading)
3’ 5’ Antiviral Pneumonia
5’ 3’
immunity Diabetes mellitus
Replication
3 ARDS
Common

IFNa Viral RNA

Ventilator-induced Obesity
4 injury Atherosclerosis
Inflammation JAK1
Translation
IkB NF-kB Zn STAT1 Immune deficiency
p50 p65 STAT2 5
P
STAT1
IRF9 RNasel PKR Other
S. Pneumoniae
IkB IKK Target genes co-infection
Zinc deficiency risk
ISRE factors
Zn p50 p65

Growth
Pro-inflammatory cytokines
(TNFa, IL-1b, etc.)
Zn

Cytokine storm

Bacterial Inhibition
Mn(II) homeostasis
Stimulation
INTERNATIONAL JOURNAL OF MOLEcULAR MEdIcINE 46: 17-26, 2020

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Curr Trends Biomedical Eng & Biosci. 2019; 19(3): 556012. DOI: 10.19080/CTBEB.2019.19.556012

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Ir Med J; Vol 113; No. 5; P81

Local production and effects of 1,25D in the respiratory tract

Cell type Conversion of 1,25D effects References

25D à 1,25D
Airway epithelium Constitutive Increases CD14 and cathelicidin; dampens IFN- Hansdottir et al. (2008, 2010)
b and chemokine response during viral
infection
Alveolar macrophages Upon activation Increases the antimicrobial peptide cathelicidin Liu et al. (2006, 2007a,b)
Dendritic cells Increases with differentiation Inhibits dendritic cell differentiation, Fritsche et al. (2003),
maturation, and function; decreases IL-12 and Sigmundsdottir et al. (2007),
increases IL-10; alters T-cell activation Piemonti et al. (2000),
Penna et al. (2005)
T-lymphocytes At least when activated Inhibits proliferation; modulates cytokine Sigmundsdottir et al. (2007),
production—inhibits Th1 and Th17 cytokines Lemire et al. (1995),
but induces TRegs Daniel et al. (2008),
Mora et al. (2008),
Pennaet al. (2005)
B-lymphocytes Unclear Inhibits proliferation of activated B-cells and Chen et al. (2007)
generation of plasma cells

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The overall content of salicylic acid and salicylates in food available on the
European market
Paulina Katarzyna K#szycka, Micha# Szkop, and Danuta Gajewska

Salicylic acid (C7H6O3, 2-hydroxybenzoic acid) and its various derivatives are
naturally present in plants and are commonly referred to as salicylates. In
Salicylates medicine, a commercially available acetylsalicylic acid (AspirinTM) is widely
Salicylates Free High Salicylates content used as an analgesic, antipyretic, anti-inflammatory, antiplatelet,
vasoprotective and antineoplastic agent.1-3
• Champignon • Lentils
• Banana • Cauliflower Different levels of salicylates in fresh and cooked vegetables
• Apples (Golden • Celery
delicious, Idared, • Strawberries Fresh vegetables Cooked vegetables
Antonowka) • Watermelon
• Pears • Buckwheat Free + bound salicylic acid Free + bound salicylic acid
SD SD
• Milk • Corn flour (µg/lg dry weight)a (µg/lg dry weight)a
• Eggs • Oat Green beans
• Chicken • Soy flour Vespa 7.69 0.07 4.54 0.20
• Millet • Brown rice Yellow beans
• Oils • Yeast Unidor 16.97 0.28 8.18 0.32
• Vinegar Broccoli
• Almond flour Calabrese 0.12
• Peppermint candy Natalino 8.88 4.33 0.11
Cauliflower
Adelanto 77.88 7.15 45.85 1.23
a The results are the m ean of three replicates

J. Agric. Food Chem., Just Accepted Manuscript. DOI: 10.1021/acs.jafc.7b04313. Publication Date (Web): 28 Nov 2017

Maternal intake (FFQ)

Intake Trimester 1 Trimester 2
Energy (mean/median) 1256.8 (653-3864) 1559 (±319.14)
Low 86 69
Normal (1700-2000) 10 23
High 4 8
Protein 47.1 (21-146) 56.11 (±15.1)
Low 73 59
Normal (60-80) 23 36
High 4 5
calcium 497.2 (57-3458) 874 (84-4159)
Low 85 68
Normal (1000-2500) 13 31
High 2 1
Iron 18.5 (3-186) 23.4 (3-250)
Low 70 51
Normal (27-45) 19 33
High 11 16
Zinc 5.4(2-19) 9.6(±2.56)
Low 96 87
Normal (12-40) 4 13
High 0 0
Folic acid 8.3 (0.6-465) 10.8 (1-247)
Low 43 32
Normal 22 37
High 35 31
Vitamin A 2521 (185-13129) 4406 (1023-16734)
Low 4 0
Normal 4 0
high 92 100
Med J Indones. 2015; 24:168-175

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Maternal Blood Mean ± SD/Median (min–max) % Maternal Blood Mean ± SD/Median (min–max) %
Vitamin A (μg/L) 470 (160–7,260) Vitamin D (μg/L) 11.3 (4.3–30.4)
Low 69.7 Low 99.6
Normal 29.9 Normal 0.4
High 0.4 Vitamin E (mg/L) 12.9 (5.1–24.4)
Folic acid (ng/dL) 19.5 (10.7–40) Normal 40.2
Normal 49.6 High 59.8
High 50.4 Zinc (μg/L) 61 (28.3–1,641.4)
Vitamin B12 (pg/mL) 414.5 (145–997) Low 81.2
Low 2.6 Normal 1.3
Normal 97.0 High 11.5
High 0.4

https://doi.org/10.13181/mji.v26i2.1617 • Med J Indones. 2017;26:109–15

Long-chain polyunsaturated fatty acid status in first-trimester pregnant women

Wibowo N, Irwinda R, Bardosono S, Prameswari N, Putri AS, Syafitri I. Med J Indones. 2018;27:155–60

• 197 pregnant women, GC-MS

Variable Blood concentration (uMol/L) N (%)

Omega-6 Variable total concentration (%) N (%)

LA
Low (< 2270) 146 (74.1) Omega-3 index (EPA+DHA)
Normal (2270 – 3850) 42 (21.3) High risk (< 4) 38 (19.3)
High (> 3850) 9 (4.6) Intermediate risk (4 – 8) 61 (28)
AA Low risk (> 8) 98 (49.7)
Low (<520) 168 (85.3)
Normal (520 – 1490) 29 (14.7) Omega 6 to omega 3 ratio
Low (< 3.4) 3 (1.5)
Omega 3
ALA Normal (3.4 – 10.7) 97 (49.2)
Low (< 50) 151 (76.6) High (> 10.7) 97 (49.2)
Normal (50 – 130) 37 (18.8) Daily maternal intake
High (> 130) 9 (4.6) PUFA 4 (0.10 – 15)
EPA
Low (< 14) 78 (39.6)
Normal (14 – 100) 89 (45.2)
High (> 100) 30 (15.2)
DHA
Low (< 30) 144 (73.1)
Normal (30 -250) 53 (26.9)

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